Personalized Medicine in Oncology - June 2015, Vol 4, No 3

A Peer-Reviewed Journal

June 2015 • Volume 4 • Number 3

PM O

BIOMARKERS • TARGETED THERAPIES • DIAGNOSTICS

Personalized Medicine in Oncology TM

INTERVIEW WITH THE INNOVATORS Understanding Implications of the Proposed FDA Regulation of Laboratory Developed Tests: An Interview with Roger D. Klein, MD, JD, and Victoria M. Pratt, PhD, FACMG, of the Association for Molecular Pathology......................................Page 138

LUNG CANCER Expanding Options for EGFR-Mutant Non–Small Cell Lung Cancer with Afatinib............................. Page 142

RET ONCOGENE IN NSCLC The RET Oncogene in Non–Small Cell Lung Cancer: Review of the Current Literature and Directions for the Future..................................................................Page 160

PMO LIVE Case: Former Smoker with Well-Differentiated Adenocarcinoma of the Lung.........................Page 167 Case Studies: Incorporating Molecular Biomarkers into Therapy for Breast Cancer Is Fraught with Difficulty......................................................... Page 168

GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies ™

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GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies ™

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LENVIMATM (lenvatinib) is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).

Visit LENVIMAinfo.com Important Safety Information Warnings and Precautions Hypertension was reported in 73% of LENVIMA-treated patients (of which 44% were ≥ Grade 3) and 16% of patients in the placebo group. Control blood pressure prior to treatment and monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly during treatment. Withhold LENVIMA for Grade 3 hypertension; resume at a reduced dose when hypertension is controlled at ≤ Grade 2.

Discontinue LENVIMA for life-threatening hypertension.

Cardiac dysfunction was reported in 7% of LENVIMA-treated patients (2% Grade 3 or greater). Monitor patients for clinical symptoms or signs of cardiac decompensation. Withhold LENVIMA for development of Grade 3 cardiac dysfunction until improved to Grade 0 or 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of cardiac dysfunction. Discontinue LENVIMA for Grade 4 cardiac dysfunction.

Arterial thromboembolic events were reported in 5% of LENVIMA-treated patients; events of Grade 3 or greater were 3%. Discontinue LENVIMA following an arterial thrombotic event. LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

4% of LENVIMA-treated patients experienced an increase in ALT and 5% experienced an increase in AST that was Grade 3 or greater. Monitor liver function before initiation and during treatment with LENVIMA. Withhold LENVIMA for the development of ≥ Grade 3 liver impairment until resolved to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hepatotoxicity. Discontinue LENVIMA for hepatic failure.

Proteinuria was reported in 34% of LENVIMA-treated patients (of which 11% were Grade 3). Monitor for proteinuria before initiation of, and periodically during treatment. Obtain a 24 hour urine protein if urine dipstick proteinuria ≥2+ is detected. Withhold LENVIMA for ≥ 2 grams of proteinuria/24 hours and resume at a reduced dose when proteinuria is <2 gm/24 hours. Discontinue LENVIMA for nephrotic syndrome.

Events of renal impairment were reported in 14% of LENVIMAtreated patients. Renal failure or impairment ≥ Grade 3 was 3% in LENVIMA-treated patients. Withhold LENVIMA for development of Grade 3 or 4 renal failure / impairment until resolved to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of renal impairment.

Events of gastrointestinal perforation or fistula were reported in 2% of LENVIMAtreated patients. Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula.

QT/QTc interval prolongation was reported in 9% of LENVIMA-treated patients (2% Grade 3 or greater). Monitor ECG in patients with congenital long QT syndrome, CHF, bradyarrhythmias, or patients taking drugs known to prolong the QT interval. Monitor and correct electrolyte abnormalities in all patients. Withhold LENVIMA for the development of ≥ Grade 3 QT interval prolongation. Resume LENVIMA at a reduced dose when QT prolongation resolves to Grade 0 or 1 or baseline.

Hypocalcemia ≥ Grade 3 was reported in 9% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment. Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia.

Reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 3 patients across clinical studies in which 1108 patients received LENVIMA. Confirm the diagnosis of RPLS with MRI. Withhold LENVIMA for RPLS until fully resolved. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of neurologic symptoms.

Hemorrhagic events occurred in 35% of LENVIMA-treated patients and in 18% of the placebo group.

The incidence of Grade 3-5 hemorrhage was similar between arms at 2% and 3%, respectively. The most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2). Discontinuation due to hemorrhagic events occurred in 1% of LENVIMA-treated patients. There was one case of fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hemorrhage. Discontinue LENVIMA in patients who experience Grade 4 hemorrhage.

LENVIMA impairs exogenous thyroid suppression. Elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. Monitor TSH levels monthly and adjust thyroid replacement medication as needed.

LENVIMA can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy.

Advise women not to breastfeed during treatment with LENVIMA. Adverse Reactions The most common adverse reactions observed in LENVIMA-treated patients vs. placebo treated patients respectively were hypertension (73% vs 16%), fatigue (67% vs 35%), diarrhea (67% vs 17%), arthralgia/myalgia (62% vs 28%), decreased appetite (54% vs 18%), weight decreased (51% vs 15%), nausea (47% vs 25%), stomatitis (41% vs 8%), headache (38% vs 11%), vomiting (36% vs 15%), proteinuria (34% vs 3%), palmar-plantar erythrodysesthesia syndrome (32% vs 1%), abdominal pain (31% vs 11%), and dysphonia (31% vs 5%).

Please see Brief Summary of Prescribing Information on the following pages.

LENVIMATM is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2015 Eisai Inc. All rights reserved.

Printed in USA/February 2015 LENV0014

S:14.5”

5.5 Proteinuria5.5 Proteinuria LENVIMA™ (lenvatinib) BRIEF SUMMARY – See package–insert for full prescribing information.

LENVIMA™ (lenvatinib) BRIEF SUMMARY See package insert for full prescribing information.

In Study 1, proteinuria was1,reported in 34% LENVIMA-treated patients and 3% patients of patients theofplacebo 1 INDICATIONS AND USAGE AND USAGE In Study proteinuria was of reported in 34% of LENVIMA-treated andin3% patients in the placebo 1 INDICATIONS group. The incidence of The Grade 3 proteinuria in LENVIMA-treated patients was 11% compared nonecompared in the to none in the LENVIMA is indicated for the treatmentfor of the patients with locally recurrent metastatic, progressive, radioactive group. incidence of Grade 3 proteinuria in LENVIMA-treated patients wasto11% LENVIMA is indicated treatment of patients with or locally recurrent or metastatic, progressive, radioactive placebo group. placebo group. iodine-refractory iodine-refractory differentiated thyroid cancer (DTC). differentiated thyroid cancer (DTC).

Monitor for proteinuria before initiation of, and initiation periodically throughout treatment.

If urinetreatment. dipstick proteinuria 2 DOSAGE AND ADMINISTRATION Monitor for proteinuria before of, and periodically throughout If urine dipstick proteinuria 2 DOSAGE AND ADMINISTRATION greater than or equal to 2+ is detected, a 24 hour obtain urine protein.

Withhold LENVIMA for ≥2 LENVIMA grams of for ≥2 grams of greater than or equal toobtain 2+ is detected, a 24 hour urine protein.

Withhold 2.1 Recommended Dose 2.1 Recommended Dose proteinuria/24 hours and resumehours at a reduced doseatwhen proteinuria is <2 gm/24 hours.

Discontinue LENVIMA proteinuria/24 and resume a reduced dose when proteinuria is <2 gm/24 hours.

Discontinue LENVIMA The recommended dose of LENVIMA is 24ofmg (two 10 ismg24capsules onecapsules 4 mg capsule) orally onceorally taken for nephrotic syndrome.

Thedaily recommended daily dose LENVIMA mg (twoand 10 mg and one 4 mgtaken capsule) once for nephrotic syndrome. daily with or without until disease progression or until unacceptable toxicity occurs. toxicity occurs.

5.6 Renal Failure and Impairment dailyfood. with Continue or withoutLENVIMA food. Continue LENVIMA until disease progression or until unacceptable 5.6 Renal Failure and Impairment Take LENVIMA atTake the LENVIMA same timeateach day. Iftime a dose is missed cannot be taken within 12 skip that the same each day. If aand dose is missed and cannot be hours, taken within 12 hours, skip that 1, eventsInofStudy In Study renal1,impairment wereimpairment reported in were 14% of LENVIMA-treated patients compared to 2% compared to 2% events of renal reported in 14% of LENVIMA-treated patients dose and take the nextand dose at the the next usualdose timeatofthe administration. dose take usual time of administration. of patients in theofplacebo group. incidence of The Grade 3 or greater renal3failure or impairment was 3% in patients in theThe placebo group. incidence of Grade or greater renal failure or impairment was 3% in Severe Renal or Hepatic Impairment LENVIMA-treatedLENVIMA-treated patients and 1% patients in the placebo group.

The primary risk factor for severe renal impairment in impairment in Severe Renal or Hepatic Impairment and 1% in the placebo group. The primary risk factor for severe renal The recommended of LENVIMAdose is 14ofmg taken orally daily in patients renalwith impairment LENVIMA-treatedLENVIMA-treated patients was dehydration/hypovolemia due to diarrhea and Thedose recommended LENVIMA is 14once mg taken orally once with dailysevere in patients severe renal impairment patients was dehydration/hypovolemia duevomiting. to diarrhea and vomiting. (creatinine clearance [CLcr] less than 30[CLcr] mL/min by thecalculated Cockroft-Gault or severe hepaticor severe hepatic Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment until resolved to Grade 0 to 1 orto Grade 0 to 1 or (creatinine clearance lesscalculated than 30 mL/min by theequation) Cockroft-Gault equation) Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment until resolved impairment (Child-Pugh C). (Child-Pugh C). baseline. Either resume at Either a reduced doseatora discontinue LENVIMA depending on thedepending severity and impairment baseline. resume reduced dose or discontinue LENVIMA on persistence the severity and persistence of renal impairment.

2.2 Dose Modifications of renal impairment.

2.2 Dose Modifications 5.7 Gastrointestinal Perforation andPerforation Fistula Formation Hypertension Hypertension 5.7 Gastrointestinal and Fistula Formation • Assess blood•pressure to pressure and periodically treatment.during Initiate or adjust Initiate medicalormanagement to management In Study gastrointestinal or fistula were reported in were 2% ofreported LENVIMA-treated patients and patients and Assessprior blood prior to during and periodically treatment. adjust medical to 1, eventsInofStudy 1, events ofperforation gastrointestinal perforation or fistula in 2% of LENVIMA-treated control blood pressure prior to and during treatment.

0.8% of patients in the placebo group. control blood pressure prior to and during treatment.

0.8% of patients in the placebo group.

• Withhold LENVIMA for Grade 3 hypertension persists despite therapy; resume therapy; Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula.

• Withhold LENVIMA for Gradethat 3 hypertension that optimal persistsantihypertensive despite optimal antihypertensive resume Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula. at a reduced doseat(see Table 1)dose when hypertension is controlled at less than or equal to Grade a reduced (see Table 1) when hypertension is controlled at less than or2.equal to Grade 2. 5.8 QT Interval5.8 Prolongation QT Interval Prolongation • Discontinue • LENVIMA for life-threatening Discontinue LENVIMA forhypertension. life-threatening hypertension.

In Study 1, QT/QTc wasprolongation reported in 9% LENVIMA-treated patients and 2% patients of patients Cardiac dysfunction or hemorrhage In interval Study 1,prolongation QT/QTc interval wasofreported in 9% of LENVIMA-treated andin2% of patients in Cardiac dysfunction or hemorrhage the placebo group.

The incidence of The QT interval prolongation of Grade 3 or greater was 32% LENVIMA-treated the placebo group. incidence of QT interval prolongation of Grade or in greater was 2% in LENVIMA-treated • Discontinue • for aDiscontinue Grade 4 event. for a Grade 4 event. patients compared to no reports in the placebo group.

Monitor electrocardiograms in patients with congenital long patients compared to no reports in the placebo group.

Monitor electrocardiograms in patients with congenital long • Withhold LENVIMA for development of Grade 3 event until improved to Grade 0 or 1 or baseline.

• Withhold LENVIMA for development of Grade 3 event until improved to Grade 0 or 1 or baseline. QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT • Either resume a reduced doseat(see Table 1)dose or discontinue LENVIMA depending on thedepending severity and • at Either resume a reduced (see Table 1) or discontinue LENVIMA on the severity andinterval, includingQTClass Iaincluding and III antiarrhythmics. interval, Class Ia and III antiarrhythmics. persistence of thepersistence adverse event. of the adverse event.

Monitor and correct electrolyte abnormalities all patients. Withhold LENVIMA for theLENVIMA development of development of Arterial thrombotic eventthrombotic event Monitor and correct electrolyteinabnormalities in all patients.

Withhold for the Arterial Grade 3 or greater QT interval prolongation.

Resume LENVIMA at a reduced dose QT prolongation Grade 3 or greater QT interval prolongation.

Resume LENVIMA at when a reduced dose when QT prolongation • Discontinue • LENVIMA following an arterial thrombotic event.thrombotic event.

Discontinue LENVIMA following an arterial resolves to Grade 0 or 1 ortobaseline. resolves Grade 0 or 1 or baseline.

Renal failure andRenal impairment or hepatotoxicity failure and impairment or hepatotoxicity 5.9 Hypocalcemia 5.9 Hypocalcemia • Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment or hepatotoxicityor until resolved until resolved • Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment hepatotoxicity In Study 1, 9% ofInLENVIMA-treated patients experienced Grade 3 or greater hypocalcemia compared to 2%compared in to Grade 0 to 1 ortobaseline.

Study 1, 9% of LENVIMA-treated patients experienced Grade 3 or greater hypocalcemia to 2% in Grade 0 to 1 or baseline. the placebo group. most cases responded to replacement dose interruption/dose reduction.

• Either resume at a reduced dose (see Table 1) or discontinue LENVIMA depending on the severity and theInplacebo group.hypocalcemia In most cases hypocalcemia respondedand to replacement and dose interruption/dose reduction.

• Either resume at a reduced dose (see Table 1) or discontinue LENVIMA depending on the severity and Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment. persistence of renal impairment or hepatotoxicity.

Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment. persistence of renal impairment or hepatotoxicity.

Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and • Discontinue • LENVIMA for hepatic failure.

Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and Discontinue LENVIMA for hepatic failure. persistence of hypocalcemia.

Proteinuria persistence of hypocalcemia.

Proteinuria 5.10 Reversible5.10 Posterior Leukoencephalopathy Syndrome • Withhold LENVIMA for ≥2 LENVIMA grams of proteinuria/24 Reversible Posterior Leukoencephalopathy Syndrome • Withhold for ≥2 grams ofhours. proteinuria/24 hours.

• Resume at a•reduced doseat(see Table 1)dose when proteinuria is <2 gm/24 hours.

Across clinical studies which studies 1108 patients received LENVIMA, there LENVIMA, were 3 reported reversible Resume a reduced (see Table 1) when proteinuria is <2 gm/24 hours.

Acrossinclinical in which 1108 patients received there events were 3of reported events of reversible • Discontinue • LENVIMA for nephrotic syndrome. posterior leukoencephalopathy syndrome (RPLS).syndrome Confirm the diagnosis of RPLS with MRI.ofWithhold RPLS until for RPLS until Discontinue LENVIMA for nephrotic syndrome. posterior leukoencephalopathy (RPLS).

Confirm the diagnosis RPLS withforMRI. Withhold Gastrointestinal perforation or fistula formation fully resolved. Upon resolution, resume at a reduced dose or discontinue LENVIMA depending on the severity and Gastrointestinal perforation or fistula formation fully resolved. Upon resolution, resume at a reduced dose or discontinue LENVIMA depending on the severity and • Discontinue • LENVIMA in patients who develop gastrointestinal or life-threatening symptoms.

Discontinue LENVIMA in patients who developperforation gastrointestinal perforation orfistula. life-threatening fistula.persistence of neurologic persistence of neurologic symptoms.

QT prolongation QT prolongation 5.11 Hemorrhagic 5.11 Events Hemorrhagic Events • Withhold LENVIMA for theLENVIMA development of Grade 3 or greater QT interval prolongation.

In Study 1, hemorrhagic occurred in 35% occurred of LENVIMA-treated patients and in 18% of theand placebo • Withhold for the development of Grade 3 or greater QT interval prolongation.

In Studyevents 1, hemorrhagic events in 35% of LENVIMA-treated patients in 18%group. of the placebo group.

• Resume LENVIMA at a reduced doseat(see Table 1)dose when QTTable prolongation to Graderesolves 0 or 1 ortobaseline. of Grade 3-5 hemorrhage similar between 2% and 3%, Therespectively. The • Resume LENVIMA a reduced (see 1) when resolves QT prolongation Grade 0 or 1 or However, baseline. the incidence However, the incidence of Grade was 3-5 hemorrhage was arms similaratbetween armsrespectively. at 2% and 3%, Reversible posterior leukoencephalopathy syndrome (RPLS) syndrome (RPLS) most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2).

Discontinuation due to Reversible posterior leukoencephalopathy most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2).

Discontinuation due to • Withhold for•RPLS until fully hemorrhagic events occurred in 1% ofoccurred LENVIMA-treated patients.

Withhold forresolved.

RPLS until fully resolved. hemorrhagic events in 1% of LENVIMA-treated patients.

• Upon resolution, resume at a reduced dose or discontinue LENVIMA depending on the severity and Across clinical studies in which 1108 patients received LENVIMA, Grade 3 or greater hemorrhage was reported • Upon resolution, resume at a reduced dose or discontinue LENVIMA depending on the severity and Across clinical studies in which 1108 patients received LENVIMA, Grade 3 or greater hemorrhage was reported persistence of neurologic symptoms. in 2% of patients.inIn2% Study 1, there In was 1 case of fatal intracranial hemorrhage among 16 patients who received persistence of neurologic symptoms. of patients.

Study 1, there was 1 case of fatal intracranial hemorrhage among 16 patients who received lenvatinib and had CNS metastases at baseline.

Manage other adverse reactions according to the instructions Table 1. BasedinonTable the absence lenvatinib and had CNS metastases at baseline.

Manage other adverse reactions according tointhe instructions 1. Basedofonclinical the absence of clinical experience, thereexperience, are no recommendations on resumption of dosing in patients with Grade 4 clinical adverse Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1.

Either resume at Either resume at there are no recommendations on resumption of dosing in patients with Grade 4 clinical adverse Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. reactions that resolve. a reduced dose ora discontinue LENVIMA depending on thedepending severity and hemorrhage. reactions that resolve. reduced dose or discontinue LENVIMA on persistence the severity of and persistenceDiscontinue of hemorrhage. Discontinue LENVIMA in patients who experience Grade 4 hemorrhage.

LENVIMA in patients who experience Grade 4 hemorrhage.

Table 1 Recommended Dose Modifications Persistent and Intolerableand Grade 2 or Grade 3 2 or5.12 Impairment of Thyroid Stimulating Hormone Suppression Table 1 Recommended Dose for Modifications for Persistent Intolerable Grade Grade 3 5.12 Impairment of Thyroid Stimulating Hormone Suppression a Adverse Reactions or Grade 4 Laboratory LENVIMA impairsLENVIMA exogenous thyroid suppression.

In Study 1, 88% of patients hadofaallbaseline Adverse Reactions or GradeAbnormalities 4 Laboratory Abnormalitiesa impairs exogenous thyroid suppression.

In all Study 1, 88% patientsthyroid had a baseline thyroid stimulating hormone (TSH) level less than or equal to 0.5 In those a normal TSH at baseline, b stimulating hormone (TSH) level less thanmU/L. or equal to 0.5patients mU/L. Inwith those patients with a normal TSH at baseline, Adverse Reaction Modification Adjusted Dose b Adverse Reaction Modification Adjusted Dose elevation of TSH elevation level above observed post baseline in 57% LENVIMA-treated patients as of 0.5 TSHmU/L levelwas above 0.5 mU/L was observed post of baseline in 57% of LENVIMA-treated patients as compared with 14% of patients receiving placebo.

Interrupt until resolved to 20 mg (two 10 mg capsules) orally compared with 14% of patients receiving placebo.

Interrupt until resolved to 20 mg (two 10 mg capsules) orally TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC. First occurrence First occurrence Grade 0-1 or baseline Monitor once daily Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC. Grade 0-1 or baseline once daily 5.13 Embryofetal 5.13Toxicity Embryofetal Toxicity 14 mg (one 10 mg14capsule mg (one 10 mg capsule Based on its mechanism action and dataoffrom animal reproduction studies, LENVIMA can cause fetal harm Interrupt until resolved to until resolved c Based onofits mechanism action and data from animal reproduction studies, LENVIMA can cause fetal harm Interrupt to plus one 4 mg capsule) Second occurrence plus one 4 mg capsule) Second occurrencec Grade 0-1 or baseline when administered to aadministered pregnant woman.

In animalwoman. reproduction studies, oral administration lenvatinib of lenvatinib when to a pregnant In animal reproduction studies, oralofadministration Grade 0-1 or baseline orally once daily orally once daily during organogenesis doses below the recommended dose resulted in embryotoxicity, duringatorganogenesis at doses below thehuman recommended human dose resulted infetotoxicity, embryotoxicity, fetotoxicity, and teratogenicityand in rats and rabbits. womenpregnant of the potential to apotential fetus. Advise Interrupt until resolved to until resolved 10 mgto(one 10 mg10capsule) teratogenicity in Advise rats andpregnant rabbits. Advise womenrisk of the risk tofemales a fetus.ofAdvise females of Interrupt mg (oneorally 10 mg capsule)reproductive orally Third occurrencecThird occurrencec Grade 0-1 or baseline potential to use effective during treatmentduring with LENVIMA forLENVIMA at least 2and weeks once daily reproductive potentialcontraception to use effective contraception treatmentand with for at least 2 weeks Grade 0-1 or baseline once daily following completion of therapy. following completion of therapy. a Initiate medicala Initiate management formanagement nausea, vomiting, or diarrhea priorortodiarrhea interruption reduction 6 ADVERSE REACTIONS medical for nausea, vomiting, priorortodose interruption or dose reduction 6 ADVERSE REACTIONS of LENVIMA of LENVIMA The following adverse reactionsadverse are discussed elsewhere in theelsewhere label. Please seelabel. the Warnings andthe Precautions b The following reactions are discussed in the Please see Warnings and Precautions Reduce dose inb succession based on the previous (24 mg, 20 mg, 14mg, mg 20 permg, day)or 14 mg per day) sections in the full prescribing Reduce dose in succession based dose on thelevel previous dose levelor(24 c sections in theinformation. full prescribing information.

Refers to the same or a different adverse reaction that requires dose modification c • Hypertension• Hypertension Refers to the same or a different adverse reaction that requires dose modification • Cardiac Dysfunction 4 CONTRAINDICATIONS • Cardiac Dysfunction 4 CONTRAINDICATIONS • Arterial Thromboembolic Events None.

• Arterial Thromboembolic Events None.

• Hepatotoxicity • Hepatotoxicity 5 WARNINGS AND PRECAUTIONS 5 WARNINGS AND PRECAUTIONS • Proteinuria • Proteinuria 5.1 Hypertension 5.1 Hypertension • Renal Failure•andRenal Impairment Failure and Impairment In Study 1 hypertension reported in 73% LENVIMA-treated patients and 16%patients of patients theofplacebo • Gastrointestinal and Fistula Formation In Studywas 1 hypertension was of reported in 73% of LENVIMA-treated and in 16% patients in the placebo • Perforation Gastrointestinal Perforation and Fistula Formation group. The median timeThe to onset of new hypertension washypertension 16 days for LENVIMA-treated patients.

• QT Interval Prolongation group. median timeor toworsening onset of new or worsening was 16 days for LENVIMA-treated patients.

• QT Interval Prolongation The incidence of The Grade 3 hypertension was 44% as compared to 4% for placebo, and the incidence of Grade 4 • 4Hypocalcemia incidence of Grade 3 hypertension was 44% as compared to 4% for placebo, and the incidence of Grade • Hypocalcemia hypertension washypertension less than 1%was in LENVIMA-treated patients and nonepatients in the placebo group.

• Reversible Posterior Leukoencephalopathy Syndrome less than 1% in LENVIMA-treated and none in the placebo group.

• Reversible Posterior Leukoencephalopathy Syndrome Control blood pressure to pressure treatmentprior withtoLENVIMA. blood pressure 1 week, then every 2 weeks Hemorrhagic•Events Controlprior blood treatmentMonitor with LENVIMA. Monitorafter blood pressure after 1 week, then every•2 weeks Hemorrhagic Events for the first 2 months, and then at least monthly thereafter during treatment with LENVIMA. Withhold LENVIMA • Impairment of Thyroid Stimulating Hormone Suppression for the first 2 months, and then at least monthly thereafter during treatment with LENVIMA. Withhold LENVIMA • Impairment of Thyroid Stimulating Hormone Suppression for Grade 3 hypertension optimal antihypertensive therapy; resume at a reduced doseatwhen hypertension 6.1 Clinical Trials for Gradedespite 3 hypertension despite optimal antihypertensive therapy; resume a reduced dose when hypertension 6.1 Experience Clinical Trials Experience is controlled at less than or equal to Grade Discontinue for life-threatening is controlled at less than or2.equal to GradeLENVIMA 2. Discontinue LENVIMA forhypertension. life-threatening hypertension. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 5.2 Cardiac Dysfunction clinical trials of aclinical drug cannot beadirectly compared to ratescompared in the clinical trials of another may notdrug reflect 5.2 Cardiac Dysfunction trials of drug cannot be directly to rates in the clinical drug trialsand of another and may not reflect In Study 1, cardiac defined as decreased leftasordecreased right ventricular cardiac function, failure, orcardiac pulmonary the rates observed practice.

In dysfunction, Study 1, cardiac dysfunction, defined left orfunction, right ventricular failure, or pulmonary theinrates observed in practice. edema, was reported in 7% of LENVIMA-treated patients (2% Grade 3 or greater) and 2% (no Grade 3 or greater) in data 1108obtained patients with advanced solid tumors whosolid received LENVIMA as a single agentas across edema, was reported in 7% of LENVIMA-treated patients (2% Grade 3 or greater) and 2% (no Grade 3 orSafety greater)data obtained Safety in 1108 patients with advanced tumors who received LENVIMA a single agent across of patients in theofplacebo group. majority of these cases inofLENVIMA-treated patients (14 of 17patients cases) were multiple usedstudies to further riskscharacterize of serious adverse reactions. median age The median age patients in theThe placebo group.

The majority these cases in LENVIMA-treated (14 of 17 cases) were clinical studies multiplewas clinical wascharacterize used to further risks ofdrug serious adverseThe drug reactions. based on findingsbased of decreased ejection fraction as assessed by echocardiography.

Six of 261 (2%) LENVIMAwas 60 years (range 21-89 years).

The21-89 dose years). range was 0.2 mgrange to 32was mg.0.2 Themg median duration of exposure in theof exposure in the on findings of decreased ejection fraction as assessed by echocardiography.

Six of 261 (2%) LENVIMAwas 60 years (range The dose to 32 mg.

The median duration treated patients in Studypatients 1 had greater than 20%greater reduction ejection fraction measured by echocardiography entire populationentire was 5.5 months. was 5.5 months. treated in Study 1 had thanin20% reduction in as ejection fraction as measured by echocardiography population compared to no patients who placebo. compared to received no patients who received placebo.

The safety data described are derivedbelow from are Study 1 which randomized (2:1) randomized patients with(2:1) radioactive The safetybelow data described derived from Study 1 which patients iodinewith radioactive iodineMonitor patientsMonitor for clinical symptoms or signs of cardiac decompensation.

Withhold LENVIMA for development refractory differentiated thyroid cancer (RAI-refractory to LENVIMADTC) (n=261) or placebo (n=131).

The median patients for clinical symptoms or signs of cardiac decompensation. Withhold LENVIMA for development refractory differentiated thyroid cancerDTC) (RAI-refractory to LENVIMA (n=261) or placebo (n=131). The median of Grade 3 cardiac untildysfunction improved tountil Grade 0 or 1 ortobaseline. at Either a reduced doseatora reduced dose treatment duration was 16.1 months for LENVIMA and 3.9 months for placebo. of dysfunction Grade 3 cardiac improved Grade 0 Either or 1 orresume baseline. resume or treatment duration was 16.1 months for LENVIMA and 3.9 months for placebo. discontinue LENVIMA depending on the severity and persistence of cardiac dysfunction.

Discontinue LENVIMA for Amongfor 261 patients who261 received LENVIMA in Study 1, median age was 64 years,age 52% were women, 80% were discontinue LENVIMA depending on the severity and persistence of cardiac dysfunction. Discontinue LENVIMA Among patients who received LENVIMA in Study 1, median was 64 years, 52% were women, 80% were Grade 4 cardiac dysfunction.

White, 18% wereWhite, Asian,18% and were 2% were Black; themselves as having Hispanic LatinoHispanic ethnicity.

Grade 4 cardiac dysfunction.

Asian, and4% 2%identified were Black; 4% identified themselves as or having or Latino ethnicity.

5.3 Arterial Thromboembolic Events In Study 1, the most common reactionsadverse observed in LENVIMA-treated patients (greaterpatients than or (greater than or 5.3 Arterial Thromboembolic Events In Study 1, theadverse most common reactions observed in LENVIMA-treated In Study 1, arterial events were reported 5% ofreported LENVIMA-treated patients and 2% patients of patients to 30%) were, decreasing frequency, hypertension, fatigue, diarrhea,fatigue, arthralgia/myalgia, In thromboembolic Study 1, arterial thromboembolic eventsinwere in 5% of LENVIMA-treated and 2% ofequal patients equalintoorder 30%)ofwere, in order of decreasing frequency, hypertension, diarrhea, arthralgia/myalgia, in the placebo group. incidence of The arterial thromboembolic events of Grade 3events or greater was 33% LENVIMAdecreased appetite, weightappetite, decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar in theThe placebo group. incidence of arterial thromboembolic of Grade or in greater was 3% in LENVIMAdecreased weight decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar treated patients and 1% in the placebo group. erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia.

The most common adverse serious adverse treated patients and 1% in the placebo group. erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. Theserious most common reactions (at least 2%) were pneumonia (4%),pneumonia hypertension (3%), and dehydration (3%).dehydration (3%).

Discontinue LENVIMA following an arterial thrombotic event.

The safety of resuming LENVIMA after an arterial reactions (at least 2%) were (4%), hypertension (3%), and Discontinue LENVIMA following an arterial thrombotic event. The safety of resuming LENVIMA after an arterial thromboembolic thromboembolic event has not been established and LENVIMA has notLENVIMA been studied in patients who have had anwho haveAdverse led to dose reductions 68%reductions of patients LENVIMA and 5%LENVIMA of patients event has not been established and has not been studied in patients had an reactionsAdverse reactions led to in dose in receiving 68% of patients receiving andreceiving 5% of patients receiving arterial thromboembolic event within the event previous 6 months. placebo; 18% of placebo; patients discontinued LENVIMA and 5%LENVIMA discontinued placebo for adverse reactions.

The most arterial thromboembolic within the previous 6 months.

18% of patients discontinued and 5% discontinued placebo for adverse reactions. The most common adversecommon reactionsadverse (at leastreactions 10%) resulting dose resulting reductions LENVIMA wereofhypertension (13%), 5.4 Hepatotoxicity (at leastin10%) in of dose reductions LENVIMA were hypertension (13%), 5.4 Hepatotoxicity proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (at least In Study 1, 4% ofInLENVIMA-treated patients experienced an increase in alanine aminotransferase (ALT) and 5% (ALT) and 5% proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (at least Study 1, 4% of LENVIMA-treated patients experienced an increase in alanine aminotransferase resulting in discontinuation LENVIMA wereofhypertension (1%)hypertension and asthenia(1%) (1%). experienced an increase in aspartate aminotransferase (AST) that was Grade or greater.

No patients in theNo patients in1%) 1%) resulting inofdiscontinuation LENVIMA were and asthenia (1%). experienced an increase in aspartate aminotransferase (AST)3that was Grade 3 or greater. the placebo group experienced Grade 3 or greater increases in ALT or AST. Across which studies 1108 in which 1108 Table 2 presents Table the percentage patients in Study 1 experiencing reactionsadverse at a higher rate inatLENVIMAplacebo group experienced Grade 3 or greater increases in ALTclinical or AST.studies Acrossinclinical 2 presentsofthe percentage of patients in Studyadverse 1 experiencing reactions a higher rate in LENVIMApatients receivedpatients LENVIMA, hepatic failure (including fatal events) wasfatal reported in 3was patients andinacute patients receiving placeboreceiving in the double-blind phase of the DTCphase study.of the DTC study. received LENVIMA, hepatic failure (including events) reported 3 patients and acutetreated patients than treated patients than patients placebo in the double-blind hepatitis was reported in 1was patient. hepatitis reported in 1 patient.

Monitor liver function before initiation of LENVIMA, then every 2 weeks for the first 2 months, and at least monthly Monitor liver function before initiation of LENVIMA, then every 2 weeks for the first 2 months, and at least monthly thereafter duringthereafter treatment.during Withhold LENVIMA for theLENVIMA development of Grade 3 or greater liver 3impairment until impairment until treatment.

Withhold for the development of Grade or greater liver resolved to Graderesolved 0 to 1 ortobaseline. at Either a reduced doseatora discontinue LENVIMA depending on thedepending on the Grade 0 Either to 1 orresume baseline. resume reduced dose or discontinue LENVIMA severity and persistence hepatotoxicity.

LENVIMA for hepatic failure. severity of and persistence ofDiscontinue hepatotoxicity.

Discontinue LENVIMA for hepatic failure.

S:14.5”

Table 2

Adverse Reactions Occurring in Patients with a Between-Group Difference of Greater than or Equal to 5% All Grades or Greater than or Equal to 2% Grades 3 and 4 LENVIMA 24 mg N=261 All Grades Grades 3-4 (%) (%)

Adverse Reaction Vascular Disorders 73 Hypertensiona Hypotension 9 Gastrointestinal Disorders Diarrhea 67 Nausea 47 b 41 Stomatitis Vomiting 36 Abdominal painc 31 Constipation 29 d 25 Oral pain Dry mouth 17 Dyspepsia 13 General Disorders and Administration Site Conditions e Fatigue 67 Edema peripheral 21 Musculoskeletal and Connective Tissue Disorders Arthralgia/Myalgiaf 62 Metabolism and Nutrition Disorders Weight decreased 51 Decreased appetite 54 Dehydration 9 Nervous System Disorders Headache 38 Dysgeusia 18 Dizziness 15 Renal and Urinary Disorders Proteinuria 34 Skin and Subcutaneous Tissue Disorders Palmar-plantar erythrodysesthesia 32 21 Rashg Alopecia 12 Hyperkeratosis 7 Respiratory, Thoracic and Mediastinal Disorders Dysphonia 31 Cough 24 Epistaxis 12 Psychiatric Disorders Insomnia 12 Infections and Infestations h 10 Dental and oral infections Urinary tract infection 11 Cardiac Disorders Electrocardiogram QT prolonged

9

Placebo N=131 All Grades Grades 3-4 (%) (%)

44 2

16 2

4 0

9 2 5 2 2 0.4 1 0.4 0.4

17 25 8 15 11 15 2 8 4

0 1 0 0 1 1 0 0 0

11 0.4

35 8

4 0

5

28

3

13 7 2

15 18 2

1 1 1

3 0 0.4

11 3 9

1 0 0

11

3

0

3 0.4 0 0

1 3 5 2

0 0 0 0

1 0 0

5 18 1

0 0 0

0

3

0

1 1

1 5

0 0

2

2

0

Includes hypertension, hypertensive crisis, increased blood pressure diastolic, and increased blood pressure b Includes aphthous stomatitis, stomatitis, glossitis, mouth ulceration, and mucosal inflammation c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, epigastric discomfort, and gastrointestinal pain d Includes oral pain, glossodynia, and oropharyngeal pain e Includes asthenia, fatigue, and malaise f Includes musculoskeletal pain, back pain, pain in extremity, arthralgia, and myalgia g Includes rash macular, rash maculo-papular, rash generalized, and rash h Includes gingivitis, oral infection, parotitis, pericoronitis, periodontitis, sialoadenitis, tooth abscess, and tooth infection A clinically important adverse reaction occurring more frequently in LENVIMA-treated patients than patients receiving placebo, but with an incidence of less than 5% was pulmonary embolism (3%, including fatal reports vs 2%, respectively). a

Table 3

Laboratory Abnormalities with a Difference of at Least ≥2% in Grade 3 - 4 Events and at a Higher Incidence in LENVIMA-Treated Patientsa

Laboratory Abnormality

Chemistry Creatinine increased Alanine aminotransferase (ALT) increased Aspartate aminotransferase (AST) increased Hypocalcemia Hypokalemia Lipase increased Hematology Platelet count decreased

LENVIMA 24 mg N=258b Grades 3-4 (%)

Placebo N=131b Grades 3-4 (%)

3 4 5 9 6 4

0 0 0 2 1 1

2

0

With at least 1 grade increase from baseline Subject with at least 1 post baseline laboratory value In addition the following laboratory abnormalities (all Grades) occurred in greater than 5% of LENVIMA-treated patients and at a rate that was two-fold or higher than in patients who received placebo: hypoalbuminemia, increased alkaline phosphatase, hypomagnesemia, hypoglycemia, hyperbilirubinemia, hypercalcemia, hypercholesterolemia, increased serum amylase, and hyperkalemia.

7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on Lenvatinib No dose adjustment of LENVIMA is recommended when co-administered with CYP3A, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) inhibitors and CYP3A and P-gp inducers.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. a b

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

Data Animal Data In an embryofetal development study, daily oral administration of lenvatinib mesylate at doses greater than or equal to 0.3 mg/kg [approximately 0.14 times the recommended human dose based on body surface area (BSA)] to pregnant rats during organogenesis resulted in dose-related decreases in mean fetal body weight, delayed fetal ossifications, and dose-related increases in fetal external (parietal edema and tail abnormalities), visceral, and skeletal anomalies. Greater than 80% postimplantation loss was observed at 1.0 mg/kg/day (approximately 0.5 times the recommended human dose based on BSA).

Daily oral administration of lenvatinib mesylate to pregnant rabbits during organogenesis resulted in fetal external (short tail), visceral (retroesophageal subclavian artery), and skeletal anomalies at doses greater than or equal to 0.03 mg/kg (approximately 0.03 times the human dose of 24 mg based on body surface area). At the 0.03 mg/kg dose, increased post-implantation loss, including 1 fetal death, was also observed. Lenvatinib was abortifacient in rabbits, resulting in late abortions in approximately one-third of the rabbits treated at a dose level of 0.5 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA).

8.2 Lactation Risk Summary It is not known whether LENVIMA is present in human milk. However, lenvatinib and its metabolites are excreted in rat milk at concentrations higher than in maternal plasma. Because of the potential for serious adverse reactions in nursing infants from LENVIMA, advise women to discontinue breastfeeding during treatment with LENVIMA. Data Animal Data Following administration of radiolabeled lenvatinib to lactating Sprague Dawley rats, lenvatinib-related radioactivity was approximately 2 times higher (based on AUC) in milk compared to maternal plasma.

8.3 Females and Males of Reproductive Potential Contraception Based on its mechanism of action, LENVIMA can cause fetal harm when administered to a pregnant woman.

Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy.

Infertility Females LENVIMA may result in reduced fertility in females of reproductive potential.

Males LENVIMA may result in damage to male reproductive tissues leading to reduced fertility of unknown duration.

8.4 Pediatric Use The safety and effectiveness of LENVIMA in pediatric patients have not been established.

Juvenile Animal Data Daily oral administration of lenvatinib mesylate to juvenile rats for 8 weeks starting on postnatal day 21 (approximately equal to a human pediatric age of 2 years) resulted in growth retardation (decreased body weight gain, decreased food consumption, and decreases in the width and/or length of the femur and tibia) and secondary delays in physical development and reproductive organ immaturity at doses greater than or equal to 2 mg/kg (approximately 1.2 to 5 times the clinical exposure by AUC at the recommended human dose). Decreased length of the femur and tibia persisted following 4 weeks of recovery. In general, the toxicologic profile of lenvatinib was similar between juvenile and adult rats, though toxicities including broken teeth at all dose levels and mortality at the 10 mg/kg/day dose level (attributed to primary duodenal lesions) occurred at earlier treatment time-points in juvenile rats.

8.5 Geriatric Use Of 261 patients who received LENVIMA in Study 1, 118 (45.2%) were greater than or equal to 65 years of age and 29 (11.1%) were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

8.6 Renal Impairment No dose adjustment is recommended in patients with mild or moderate renal impairment. In patients with severe renal impairment, the recommended dose is 14 mg taken once daily. Patients with end stage renal disease were not studied.

8.7 Hepatic Impairment No dose adjustment is recommended in patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, the recommended dose is 14 mg taken once daily.

10 OVERDOSAGE There is no specific antidote for overdose with LENVIMA. Due to the high plasma protein binding, lenvatinib is not expected to be dialyzable. Adverse reactions in patients receiving single doses of LENVIMA as high as 40 mg were similar to the adverse events reported in the clinical studies at the recommended dose.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).

Hypertension: Advise patients to undergo regular blood pressure monitoring and to contact their health care provider if blood pressure is elevated.

Cardiac Dysfunction: Advise patients that LENVIMA can cause cardiac dysfunction and to immediately contact their healthcare provider if they experience any clinical symptoms of cardiac dysfunction such as shortness of breath or swelling of ankles.

Arterial Thrombotic Events Advise patients to seek immediate medical attention for new onset chest pain or acute neurologic symptoms consistent with myocardial infarction or stroke.

Hepatotoxicity: Advise patients that they will need to undergo lab tests to monitor for liver function and to report any new symptoms indicating hepatic toxicity or failure.

Proteinuria and Renal Failure/Impairment: Advise patients that they will need to undergo regular lab tests to monitor for kidney function and protein in the urine.

Gastrointestinal perforation or fistula formation: Advise patients that LENVIMA can increase the risk of gastrointestinal perforation or fistula and to seek immediate medical attention for severe abdominal pain.

Hemorrhagic Events: Advise patients that LENVIMA can increase the risk for bleeding and to contact their health care provider for bleeding or symptoms of severe bleeding.

Embryofetal Toxicity: Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy.

Lactation: Advise nursing women to discontinue breastfeeding during treatment with LENVIMA.

LENVIMA™ is a trademark of Eisai R&D Management Co., Ltd. and is licensed to Eisai Inc. © 2015 Eisai Inc. All rights reserved. Printed in USA/February 2015 LENV0176

JUNE 2015

VOLUME 4, NUMBER 3

TABLE OF CONTENTS INTERVIEW WITH THE INNOVATORS

138

Understanding Implications of the Proposed FDA Regulation of Laboratory Developed Tests

An Interview with Roger D. Klein, MD, JD, and Victoria M. Pratt, PhD, FACMG, of the

Association for Molecular Pathology PMO speaks with Drs Klein and Pratt from the Association for Molecular Pathology

about their recent white paper entitled “A Molecular Diagnostic Perfect Storm: The

Convergence of Regulatory & Reimbursement Forces that Threaten Patient Access to

Innovations in Genomic Medicine.” HEMATOLOGIC MALIGNANCIES LUNG CANCER

142 Expanding Options for EGFR-Mutant Non–Small Cell Lung Cancer with Afatinib

Elizabeth Tsui; Karen L. Reckamp, MD, MS

The authors examine the data from the use of afatinib for the treatment of NSCLC. BRAF ONCOGENE IN NSCLC

152 BRAF Mutations: An Old Oncogene and a New Target in Non–Small Cell Lung Cancer

Shihfan Yeh, MD; Lyudmila Bazhenova, MD

The authors provide a review focusing on BRAF mutations in NSCLC, which are much more diverse and show a wide spectrum of kinase activity compared with those found in melanoma, and include therapy options for this subset of patients.

RET ONCOGENE IN NSCLC

160 The RET Oncogene in Non–Small Cell Lung Cancer: Review of the Current

Literature and Directions for the Future

Rebecca A. Shatsky, MD; Lyudmila Bazhenova, MD

The authors discuss the RET proto-oncogene, one of the newest drug-targetable genetic mutations in lung cancer that is just beginning to be explored in human clinical trials.

OUR MISSION Personalized Medicine in Oncology provides the bridge between academic research and practicing clinicians by demonstrating the immediate implications of precision medicine – including advancements in molecular sequencing, targeted therapies, and new diagnostic modalities – to the management of patients with cancer, offering oncologists, oncology nurses, payers, researchers, drug developers, policymakers, and all oncology stakeholders the relevant practical information they need to improve cancer outcomes. This journal translates the new understanding of the biology of cancer into the day-to-day management of the individual patient with cancer, using a patient’s unique genetic makeup to select the best available therapy.

OUR VISION Our vision is to transform the current medical model into a new model of personalized care, where decisions and practices are tailored for the individual – beginning with an incremental integration of personalized techniques into the conventional practice paradigm currently in place.

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PUBLISHING STAFF Vice President/Group Publisher Russell Hennessy rhennessy@the-lynx-group.com Manager, Client Services Travis Sullivan tjsullivan@the-lynx-group.com Editorial Director Kristin Siyahian ksiyahian@the-lynx-group.com Strategic Editor Robert E. Henry Senior Copyeditor BJ Hansen Copyeditor Rosemary Hansen Production Manager Marie RS Borrelli The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Director, Strategy & Program Development John Welz Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistants Lora LaRocca Wayne Williams Content Marketing Director Samantha Weissman Web Content Manager Anthony Trevean Content Digital Manager Allison Musante Digital Programmer Michael Amundsen Jr Digital Media Specialist Charles Easton IV Meeting & Events Planner Linda Mezzacappa Project Managers Deanna Martinez Jeremy Shannon Project Coordinator Rachael Baranoski IT Manager Kashif Javaid Sales Assistant Aadam Mohamed Administrative Assistant Amanda Hedman Office Coordinator Robert Sorensen Green Hill Healthcare Communications, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-656-7935 • fax: 732-656-7938

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BECAUSE THERE IS SO MUCH HANGING IN THE BALANCE COUNT ON THE FIRST TARGETED NGS PROFILE FOR LUNG CANCER FROM GENOPTIX When it comes to your patient’s care, there is no time to waste sifting through excess data. Genoptix’s Lung Molecular Profile identifies all therapeutically relevant genomic alterations in a single profile.

Focus on what matters — choose the Lung Molecular profile from Genoptix. www.genoptix.com | 800.755.1605

©2015 Genoptix, Inc. Genoptix® is a registered trademark of Genoptix, Inc.

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REGISTER

TODAY

TABLE OF CONTENTS

(Continued)

PMO LIVE

167 168

Case: Former Smoker with Well-Differentiated Adenocarcinoma of the Lung Case Studies: Incorporating Molecular Biomarkers into Therapy for Breast Cancer Is Fraught with Difficulty These case studies, exemplifying the personalized medicine approach, were presented

by Roy S. Herbst, MD, PhD, and Hope S. Rugo, MD, respectively, at the Third Annual PMO Live conference.

EUROPEAN LUNG CANCER CONFERENCE

173

DNA Blood Testing May Be an Alternative to Tumor Sampling for Identifying EGFR Mutations PTIENT NAVIGATION

AMERICAN ASSOCIATION FOR CANCER RESEARCH

174

PARP Inhibitor and PI3K Inhibitor Combo in Breast and Ovarian Cancers

175

Genomic Sequencing for Pancreatic Cancer

CLINICAL TRIAL

177

ASCO Launches First-Ever Clinical Trial: Aims to Learn from Patients with Advanced Cancer Who Lack Standard Treatment Options

JULY 22-25, 2015 THE WESTIN SEATTLE SEATTLE, WASHINGTON

Personalized Medicine in Oncology is included in the following indexing and database services: Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO research databases

Personalized Medicine in Oncology, ISSN 2166-0166 (print); ISSN applied for (online) is published 6 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copy­right ©2015 by Green Hill Health­care Com­muni­cations, LLC. All rights reserved. Personalized Medicine in Oncology logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

EDITORIAL CORRESPONDENCE should be ad­dressed to EDITORIAL DIRECTOR, Personalized Medicine in Oncology (PMO), 1249 South River Road, Suite 202A, Cranbury, NJ 08512. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $50.00; institutions, $90.00; single issues, $5.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPART­MENT, Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in PMO do not necessarily reflect those of the editorial board, the editorial director, or the publishers. Publication of an advertisement or other product mention in PMO should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the editorial board nor the publishers assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the editorial director.

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Image: Colored scanning electron micrograph (SEM) of a lymphoma cancer cell.

One goal: discovering breakthrough medicines to combat cancer.

We are excited to announce the launch of TAKEDA ONCOLOGY formerly known as MILLENNIUM: THE TAKEDA ONCOLOGY COMPANY. Our mission is unchanged as we strive to reset expectations for patients with cancer worldwide through our commitment to science, breakthrough innovation and passion for improving their lives.

This singular focus drives our aspiration to discover breakthrough oncology therapies, designed with patient needs in mind.

By concentrating the power of leading scientific minds and the vast resources of a global pharmaceutical company, we are finding innovative ways to improve the treatment of cancer. We’ve built a portfolio of paradigm-changing therapies and a leading oncology pipeline. While we’ve made great strides in our fight against cancer, we are determined to do more—to work harder, to achieve greater—and to do it with the same passion, agility and entrepreneurial spirit that has always been at the heart of our culture and made us the leaders in oncology that we are today.

We know that our mission is not a quick or easy one but we are up to the task: we aspire to cure cancer.

Takeda Oncology is Proud to Partner with Personalized Medicine in Oncology.

To learn more, visit us at takedaoncology.com. @TakedaOncology ©2015 Millennium Pharmaceuticals, Inc. All rights reserved.

EDITORIAL BOARD

EDITORS IN CHIEF Sanjiv S. Agarwala, MD St. Luke’s Hospital Bethlehem, Pennsylvania

Prostate Cancer Oliver Sartor, MD Tulane University New Orleans, Louisiana

Al B. Benson III, MD, FACP, FASCO Northwestern University Chicago, Illinois

EDITORIAL BOARD Gregory D. Ayers, MS Vanderbilt University School of Medicine Nashville, Tennessee

SECTION EDITORS Biomarkers Pranil K. Chandra, DO PathGroup Brentwood, Tennessee

Lyudmila Bazhenova, MD University of California, San Diego San Diego, California

Darren Sigal, MD Scripps Clinic Medical Group San Diego, California Breast Cancer Edith Perez, MD Mayo Clinic Jacksonville, Florida Hematologic Malignancies Gautam Borthakur, MD The University of Texas MD Anderson Cancer Center Houston, Texas Pathology David L. Rimm, MD, PhD Yale Pathology Tissue Services Yale University School of Medicine New Haven, Connecticut Drug Development Igor Puzanov, MD Vanderbilt University Vanderbilt-Ingram Cancer Center Nashville, Tennessee Lung Cancer Vincent A. Miller, MD Foundation Medicine Cambridge, Massachusetts Predictive Modeling Michael Kattan, PhD Case Western Reserve University Cleveland, Ohio Gastrointestinal Cancer Eunice Kwak, MD Massachusetts General Hospital Cancer Center Harvard Medical School Boston, Massachusetts Melanoma Doug Schwartzentruber, MD Indiana University Simon Cancer Center Indianapolis, Indiana

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Leif Bergsagel, MD Mayo Clinic Scottsdale, Arizona Mark S. Boguski, MD, PhD Harvard Medical School Boston, Massachusetts Gilberto Castro, MD Instituto do Câncer do Estado de São Paulo São Paulo, Brazil Madeleine Duvic, MD The University of Texas MD Anderson Cancer Center Houston, Texas Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Center Cleveland, Ohio Steven D. Gore, MD The Johns Hopkins University School of Medicine Baltimore, Maryland Gregory Kalemkerian, MD University of Michigan Ann Arbor, Michigan Howard L. Kaufman, MD Cancer Institute of New Jersey New Brunswick, New Jersey Katie Kelley, MD UCSF School of Medicine San Francisco, California Minetta Liu, MD Mayo Clinic Cancer Center Rochester, Minnesota

Nikhil C. Munshi, MD Dana-Farber Cancer Institute Boston, Massachusetts Steven O’Day, MD John Wayne Cancer Institute Santa Monica, California Rafael Rosell, MD, PhD Catalan Institute of Oncology Barcelona, Spain Steven T. Rosen, MD, FACP Northwestern University Chicago, Illinois Hope S. Rugo, MD University of California, San Francisco San Francisco, California Lee Schwartzberg, MD The West Clinic Memphis, Tennessee John Shaughnessy, PhD University of Arkansas for Medical Sciences Little Rock, Arkansas Lillie D. Shockney, RN, BS, MAS Johns Hopkins University Baltimore, Maryland Lawrence N. Shulman, MD Dana-Farber Cancer Institute Boston, Massachusetts Jamie Shutter, MD South Beach Medical Consultants, LLC Miami Beach, Florida David Spigel, MD Sarah Cannon Research Institute Nashville, Tennessee Moshe Talpaz, MD University of Michigan Medical Center Ann Arbor, Michigan Sheila D. Walcoff, JD Goldbug Strategies, LLC Rockville, Maryland Anas Younes, MD The University of Texas MD Anderson Cancer Center Houston, Texas

Kim Margolin, MD University of Washington Fred Hutchinson Cancer Research Center Seattle, Washington Gene Morse, PharmD University at Buffalo Buffalo, New York

Personalized Medicine in Oncology

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EDITORIAL LETTER TO OUR READERS

The Increasingly Important Role of Pathology in Oncology Patient Care Dear Colleague,

W

e are pleased to offer this issue of Personalized Medicine in Oncology (PMO) to you, our reading community. Since the onset of the personalized medicine era, we have repeatedly heard about the importance of the multidisciplinary team to include physicians, nurses, pharmacists, pathologists, social workers, and patients. Of late, we have been intrigued by the growing role of the pathologist. This era of breakthroughs in genetic medicine has placed pathologists at the forefront, Al B. Benson III, delivering essential diagnostic clinical data to help determine the best treatment options for patients. MD, FACP, FASCO There has been much debate over the proposal by the FDA to regulate laboratory developed tests. In this issue of PMO, the Interview with the Innovators department features our exchange with Drs Klein and Pratt of the Association for Molecular Pathology about the implications of this proposal (page 138).

Also in this issue, Ms Tsui and Dr Reckamp contribute their paper entitled “Expanding Options for EGFR-Mutant Non–Small Cell Lung Cancer The pathologist is at the with Afatinib” (142), and we continue to explore the changing landscape of forefront, delivering essential oncology care through the fascinating science behind oncogenic driver mudiagnostic clinical data to help tations and their implications for patient care. Drs Yeh and Bazhenova at the University of California, San Diego, present “BRAF Mutations: An Old determine the best treatment Oncogene and a New Target in Non–Small Cell Lung Cancer” (page 152); options for patients. and Drs Shatsky and Bazhenova present “The RET Oncogene in Non–Small Cell Lung Cancer: Review of the Current Literature and Directions for the Future” (page 160).

We are dedicated to providing in-depth articles of the most compelling research from the personalized medicine front for all of us involved in patient care. It is our hope this information assists you in providing the best care for your patients.

Sincerely,

Al B. Benson III, MD, FACP, FASCO Coeditor in Chief Personalized Medicine in Oncology

Vol 4, No 3

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JULY 22-25, 2015 • THE WESTIN SEATTLE Conference Chairs

• SEATTLE, WASHINGTON

PMO Live is an annual joint meeting of the Global Biomarkers Consortium and World Cutaneous Malignancies Congress focused on personalized and precision medicine in oncology.

Expert speakers and thought leaders will explore the discovery and application of new drug regimens, biomarkers, and diagnostics in addition to the rapid changes to the healthcare system and their impact on oncology care and access for patients.

EDUCATIONAL OBJECTIVES Sanjiv S. Agarwala, MD

Professor of Medicine Temple University School of Medicine Chief, Medical Oncology & Hematology St. Luke’s Cancer Center Bethlehem, PA

Jorge E. Cortes, MD

Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

After completing this activity, the participant should be better able to:

▶

Assess emerging data and recent advances in the discovery of molecular biomarkers and their impact on the management of patients with solid tumors and hematologic malignancies

▶ ▶

Incorporate unique molecular pathways in the targeted therapy of cancer

▶

Integrate existing and emerging data on the most effective use of molecular biomarkers into personalized treatment strategies for patients with solid tumors and hematologic malignancies

▶

Describe the regulatory and economic considerations in providing personalized care in oncology

▶

Apply emerging data on the molecular biology and pathophysiology of malignant melanoma, CTCL, BCC, and MCC into targeted therapy

▶

Formulate personalized treatment strategies for patients with metastatic melanoma, CTCL, BCC, and MCC based on patient and tumor characteristics and current treatment standards

▶

Integrate emerging data and recent advances with new molecular targets for the treatment of patients with metastatic melanoma, CTCL, BCC, and MCC into clinical practice

▶

Identify new technologies for the prevention and early detection of cutaneous malignancies

Describe the types of cancer biomarker tests that are clinically available, which tests to order for specific patients, and how to use the test results in informing personalized therapy

PHYSICIAN CONTINUING MEDICAL EDUCATION* Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the Postgraduate Institute for Medicine and Center of Excellence Media, LLC. The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians.

PHYSICIAN CREDIT DESIGNATION Hope S. Rugo, MD

Professor of Medicine Director, Breast Oncology and Clinical Trials Education UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, CA

Hope S. Rugo, M.D. Professor of Medicine

The Postgraduate Institute for Medicine designates this live activity for a maximum of 20.5 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. *This CME/CE activity complies with all requirements of the federal Physician Payment Sunshine Act. If a reportable event is associated with this activity, the accredited provider managing the program will provide the appropriate physician data to the Open Payments database.

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AGENDA* Molecular Biomarkers for Precision Medicine in Oncology: Recent Advances and Future Perspectives

Wednesday

July 22

2:00 PM – 2:15 PM

Welcome and Introduction

2:15 PM – 3:45 PM

General Session I: A Primer on the Clinical Application of Molecular Biomarkers: What to Order and How to Use the Results

3:45 PM – 4:15 PM

Keynote Presentation: Exploring Molecular Pathways in Cancer

4:15 PM – 4:30 PM

Break

4:30 PM – 5:00 PM

General Session II: What’s New in Cancer Biomarker Research?

5:00 PM – 6:30 PM

General Session III: Case Studies—Innovative Molecular Pathways and Biomarkers in Treating Solid Tumors

6:30 PM – 8:30 PM

Thursday

“Meet the Experts” Cocktail Reception, Networking, Poster and Exhibits Viewing

July 23

7:00 AM – 8:00 AM

Product Theater Breakfast

8:00 AM – 8:15 AM

Break

8:15 AM – 8:35 AM

Review of Yesterday’s Presentations and a Preview of Today

8:35 AM – 9:15 PM

Keynote Presentation: Targeting Genetic Drivers in Premalignancy

9:15 AM – 10:35 AM

General Session IV: Case Studies—Innovative Molecular Pathways and Biomarkers in Treating Hematologic Malignancies

10:35 AM – 10:55 AM

Keynote Presentation: An Industry Perspective on the Use of Biomarkers in Cancer: How Are They Really Used?

World Cutaneous Malignancies Congress

Friday

July 24

7:30 AM – 8:30 AM

Product Theater Breakfast

8:30 AM – 8:45 AM

Break

8:45 AM – 9:00 AM

Welcome and Introduction to WCMC 2015

9:00 AM – 10:20 AM

General Session I: Clinical Presentations of Cutaneous Malignancies

10:20 AM – 11:40 AM

General Session II: Understanding the Molecular Biology of Cutaneous Malignancies: Application to Clinical Practice

11:40 AM – 11:55 AM

Break

11:55 AM – 12:55 PM

Product Theater Lunch

12:55 PM – 1:10 PM

Break

1:10 PM – 2:30 PM

General Session III: Surgical and Locoregional Therapies

2:30 PM – 4:00 PM

General Session IV: Current Approaches to Therapy—Case Studies in Malignant Melanoma

4:00 PM – 5:30 PM

“Meet the Experts” Cocktail Reception and Poster Presentations

Saturday

July 25

7:30 AM – 8:30 AM

Product Theater Breakfast

8:30 AM – 8:45 AM

Break

8:45 AM – 9:00 AM

Review of Yesterday’s Presentations and a Preview of Today

9:00 AM – 9:45 AM

General Session V: Current Approaches to Therapy—Case Studies in Nonmelanoma Cutaneous Malignancies

9:45 AM – 10:45 AM

General Session VI: Emerging Therapies in Advanced Melanoma

10:55 AM – 11:50 PM

General Session V: Molecular Biomarkers for the Early Detection of Cancer

10:45 AM – 11:05 AM

Keynote Lecture: Genetic Testing for Melanoma: BRAF, NRAS, C-Kit, and Beyond

11:50 AM – 12:05 PM

Break

11:05 AM – 11:50 AM

General Session VII: Emerging Therapies in Advanced Nonmelanoma Cutaneous Malignancies

11:50 AM – 12:10 PM

General Session VIII: Advances in the Prevention and Early Detection of Cutaneous Malignancies

12:10 PM – 12:25 PM

Poster Presentation – Winner of Best Poster Abstract, WCMC

12:25 PM – 12:40 PM

Closing Remarks

12:05 PM – 1:05 PM

Product Theater Lunch

1:05 PM – 2:20 PM

Break

2:20 PM – 2:50 PM

Keynote Presentation: The Impact of Molecular Biomarkers on Clinical Trials

2:50 PM – 3:20 PM

General Session VI: Regulatory and Economic Aspects of Precision Medicine

3:20 PM – 3:35 PM

Poster Presentation – Winner of Best Poster Abstract, GBC

3:40 PM – 5:40 PM

“Meet the Experts” Reception—A Parting Opportunity for Informal Communication and Networking, and Viewing of Posters and Exhibits

Jointly provided by Postgraduate Institute for Medicine and Center of Excellence Media, LLC

12:45 PM – 1:25 PM

“Meet the Experts” Lunch—A Parting Opportunity for Informal Communication and Networking *Agenda subject to change.

Fees: Industry regular - $700 full conference HCP regular $400 full conference $200 2-day pass (7/22 – 7/23) $200 2-day pass (7/24 – 7/25)

Student regular $175 full conference $90 2-day pass (7/22 – 7/23) $90 2-day pass (7/24 – 7/25)

Register Today at www.etouches.com/pmolive2015

INTERVIEW WITH THE INNOVATORS

Understanding Implications of the Proposed FDA Regulation of Laboratory Developed Tests An Interview with Roger D. Klein, MD, JD, and Victoria M. Pratt, PhD, FACMG, of the Association for Molecular Pathology

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hortly after the Food and Drug Administration (FDA) released its proposed draft guidance for regulating laboratory developed tests, including molecular diagnostic testing, the Association for Molecular Pathology (AMP) published a white paper addressing the potential consequences of regulatory and reimbursement dynamics that threaten patient Roger D. Klein, care. The paper, titled “A Molecular DiagnosMD, JD tic Perfect Storm: The Convergence of Regulatory & Reimbursement Forces that Threaten Patient Access to Innovations in Genomic Medicine,” addresses the consequences of this gathering perfect storm of regulatory and reimbursement forces impacting molecular diagnostic testing. The white paper offers numerous recommendations designed to preserve patient access to appropriate testing and mitiVictoria M. Pratt, gate burgeoning negative impact on healthPhD, FACMG care. This paper is available online at http:// amp.org/publications_resources/position_ statements_letters/PerfectStorm.cfm.

AMP holds that medical professionals in universities, cancer centers, clinical laboratories, and pharmaceutical/manufacturing companies across the country have honored the public trust in the Human Genome Project by developing hundreds of innovative diagnostic tests and therapies that are advancing modern med-

icine in ways that would have otherwise been impossible without this breakthrough in genetic research.

They view the proposed regulation by the FDA and the reimbursement policies of the Centers for Medicare & Medicaid Services (CMS) as barriers that could prevent continued progress in this arena.

Essentially, they say the new policies inappropriately classify laboratory developed procedures (LDPs) as medical devices and apply existing medical device regulations, which were enacted for regulation of medical device manufacturers, to the activities of clinical laboratories that perform services using LDPs. If implemented, the FDA’s proposed framework would unjustifiably impose new, burdensome, and in some cases duplicative requirements on clinical laboratories and the medical professionals who perform essential services within them. Meanwhile, the CMS, the nation’s largest insurer, may deny coverage or reduce payment for several medically necessary molecular pathology tests. Medicare coverage policies are frequently adopted by the private sector. Unfortunately, healthcare providers—those developing and delivering innovative diagnostic tests—along with patients, who are the ultimate intended beneficiaries, are caught in the middle.

PMO recently had the pleasure of speaking with 2 members of AMP—Dr Roger G. Klein, and lead author of the “Perfect Storm” paper, Dr Victoria M. Pratt.

PMO Can you please provide a synopsis of the issue Dr Klein is Chair of the AMP Professional Relations Committee and covered in your paper, “A Molecular Diagnostic Perfect Medical Director of Molecular Oncology at the Robert J. Tomsich Storm: The Convergence of Regulatory & ReimbursePathology & Laboratory Medicine Institute, The Cleveland Clinic Foundation. ment Forces that Threaten Patient Access to InnovaDr Pratt is a member of the AMP Professional Relations Committee, tion in Genomic Medicine”? the Chair Elect of the AMP Program Committee, and Director, Dr Pratt We at AMP feel that laboratory developed Pharmacogenomics Laboratory in the Department of Medical and tests are more accurately described as laboratory develMolecular Genetics at Indiana University School of Medicine. oped procedures (LDPs) and, with some improvement

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under CLIA [Clinical Laboratory Improvement Amendments], state, and other governing agencies, there is more than adequate oversight of these procedures already in place. Currently, there are multiple forces within the FDA endorsing FDA oversight of laboratory procedures as well as the CMS looking at reducing reimbursement. There are high costs associated with FDA oversight, costs in addition to the cost that we already incur for maintaining our other regulatory agencies that inspect and oversee the laboratory industry. Considering this, along with lack of reimbursement, we’re looking at the potential that laboratory testing, especially by molecular pathologists, may no longer be offered.

Dr Klein The focus of the white paper is the headwinds that the folks who are doing clinical laboratory testing are facing right now. Those headwinds include the proposed FDA regulations as well as reimbursement issues. We’ve had substantial downward pressure on reimbursement as well as significantly increased stringency with respect to coverage decisions.

Then there’s also regulation that’s imposed through the clinical laboratory provisions of the Protecting Access to Medicare Act, which places extremely arduous reporting burdens on nonbundled laboratory testing.

The statute requires labs to report extremely granular payment data to the CMS. These data include all prices and volumes for each test for every payer. All these forces are coalescing to produce this enormous headwind.

Most clinical laboratories lack the resources and don’t have the expertise to file FDA submissions for their tests. So if the FDA begins implementing regulations and requires premarket submissions, the result will be that affected tests are not going to be offered by most of the AMP members.

Dr Pratt Some of the concern is simply the associated costs. The lab incurs cost for proficiency tests, for CAP [College of American Pathologists] accreditation, for maintenance contracts, and now potentially the FDA’s fees, because all of these submissions have user fees as mandated under law that the laboratories would be required to pay on top of everything else. With the lack of reimbursement, there’s no return on investment here. We’re working in the negative values.

PMO The FDA and other federal agencies propose that the complexity of LPDs, particularly genomic sequencing, warrant a regulatory framework for the FDA to ensure that LDPs are properly validated. This appears to be a hypothetical concern by the FDA rather than a response to real-world examples of trouble that’s happened lacking these regulations. Do you see this as an accurate read on the problem?

Dr Pratt AMP and others have asked the FDA to

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provide examples of where there’s a problem, and they’ve quoted from The New York Times 2, maybe 3 cases where perhaps not all the data are well documented. One example is a technology issue at Dartmouth and the CDC [Centers for Disease Control and Prevention], where Dartmouth used an assay that had a lower limit of detection than the CDC assay, so there was a concern that there were false-positives and false-negatives associated with the various tests.

There’s not good documentation that a problem exists out there that the FDA is trying to fix. It’s important to note that AMP doesn’t come to the table suggesting that there’s absolutely nothing wrong with the current programs that are in place. It’s been acknowledged that there’s room for some improvement in the current structure. We believe we should not implement something that is overly burdensome for a program that is already working well.

Today, there are multiple forces within the FDA endorsing FDA oversight of laboratory procedures as well as the CMS looking at reducing reimbursement.

Dr Klein I completely agree. Our position as an organization is that we support modernization of the CLIA regulations, which were originally written in the early ’90s. We believe that most laboratory testing performed by reputable laboratories under most circumstances is of high quality. Examination of proficiency testing data from CAP and a dearth of lawsuits against clinical laboratory providers support that contention.

If you look at our litigious society, you rarely see a laboratory getting sued because of faulty laboratory tests. Our system is currently very heavily dependent on having high-quality professionals directing the laboratories, and in most cases it works well. One of the criticisms the FDA has is that the CLIA regulations themselves do not mandate, or do not explicitly require, that tests that are offered have clinical validity. Some of the agencies, like the CAP- and CLIA-exempt states like New York, actually do require a demonstration of clinical validity for molecular pathology tests.

This is a very important topic, especially in oncology. In cancer diagnostics there may in fact be tests offered for which the clinical usefulness is uncertain, or in unusual cases for which the clinical meaning of the biomarker itself is unclear. As an organization, we’re willing to admit that there may be offerings out there for biomarkers that are of dubious value. How-

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ever, the appropriate regulatory mechanism for addressing this issue is CLIA, rather than the imposition of medical device regulations on clinical laboratories.

In fact, that is what the FDA is talking about doing.

The agency has proposed taking preexisting medical device regulations and superimposing them on activities of clinical laboratories.

PMO Would you say that the core of the conflict arises from the definition of an LPD as a medical service versus a test?

Dr Klein The CLIA regulations are geared toward laboratory services and oversight of the provision of laboratory services. These are medical services; they are patient services. CMS approaches these activities within that paradigm. The FDA regulations are geared toward manufacturers of medical devices that are designed, developed, manufactured, boxed, labeled, and distributed in interstate commerce to laboratories across the country.

The agency has proposed taking preexisting medical device regulations and superimposing them on activities of clinical laboratories.

Further, I think the interpretation component should not be overlooked. The role of the molecular pathologist is not just running a device or running a test. There is brain power, there is training, many years of extensive training, and successful completion of various examinations to ensure that the professional is qualified to not only run but interpret these tests.

Dr Pratt I agree. The lab is not a box that spits out an answer. There’s a lot of professional work that’s done behind the scenes to give that interpretation.

Dr Klein I think this is a critical point, because one of the things the FDA is doing here is to make an artificial distinction between the “test,” which is what they’re calling a device, and the work of the professionals who actually developed those tests, continually monitor them, improve them, use them in patient care, and interpret and report their results in this context.

While the dichotomy between test manufacturer and operation exists in the manufacturing world, it really doesn’t exist in a clinical laboratory. The laboratory director who’s looking at these tests is responsible for all aspects of them from start to finish, including test design, development, and validation, and we have very highly skilled and highly trained people who are doing this work.

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PMO How does the FDA state the need for the proposed regulations?

Dr Pratt In my opinion, there are unseen pressures, some of which stem from the direct-to-consumer testing market, which is essentially gone with the exception of 23andMe. I think there is pressure from manufacturers concerned about laboratories using their test, because often their tests are for a very narrow indication. For example, there’s a BRAF test for colon cancer, but there’s also a BRAF test for melanoma. These are different BRAF tests, and you can’t mix and match those so that an LDP actually will validate both on 1 instrument.

I think there is pressure from manufacturers that want better return on investment for going through the FDA process. They believe there’s an uneven playing field. But I would point out that manufacturers aren’t inspected routinely by CAP, CLIA, and other state agencies. I know in my previous lab, we were inspected up to 3 or 4 times a year by various internal groups and external agencies.

Dr Klein As an organization, we understand that, particularly in the molecular world, technology is advancing very rapidly. There are many new tests and offerings out there that potentially could be criticized as not yet having sufficient data to demonstrate that they’re clinically valuable for patients. But I think it’s important to understand that as an organization, we are patient advocates and, therefore, want what’s best for the patient. Again, we’re not saying that there are zero problems. What we’re saying is that the current system works well for most testing, and that to improve the system for the current era, it requires more of a surgical scalpel than a mallet. If the FDA imposes a heavy-handed system that’s designed for manufacturers on clinical laboratories, that would risk patient access to essential, innovative services.

PMO Are you satisfied with the process of dialogue between yourselves and the FDA, or is there room for improvement there?

Dr Klein I chair AMP’s Professional Relations Committee, and I want you to understand that we have had a very good working relationship with the FDA for a number of years. The FDA recognizes the expertise that resides in our organization. Our members serve on FDA advisory committees. In fact, FDA personnel are members of our organization. So although we disagree on this particular issue, it is not that we don’t maintain good relationships with the FDA or that we don’t respect the people there. Quite the contrary, we respect them very much. What we are trying to do is to work together with the FDA and the CMS for the benefit of the patient. We simply don’t agree on this particular

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issue, probably because of our in-depth understanding of what it takes to operate a laboratory, our understanding of the field, the important benefits molecular testing brings to patients, and the overall quality with which the services appear to be provided. Basically, you’re hearing the laboratory professional’s perspective relative to that of the FDA, but you can rest assured that there is an ongoing dialogue that is actually quite friendly and civil.

PMO Where is the meeting point? Can you summarize how you propose moving ahead?

Dr Pratt Some of our recommendations focus on updating the existing regulatory agency CLIA. We believe that CLIA can be improved to address the concerns that the FDA is trying to address.

There’s adverse reporting, which could be done through CLIA. CLIA could add guidance documentation around clinical validity. There is already language in federal law for CLIA around this concept, but it could be more explicit.

The FDA is concerned that they do not have knowledge of all the available tests that are already being performed in the labs across the United States. Quite the contrary, that information resides in CLIA; however, CMS cannot easily pull those data from their information system. This is another improvement to be made.

PMO Do you have any insights as to how this impacts the field of oncology specifically?

Dr Klein One of the areas that we’re concerned with now is the implementation of next-generation sequencing, a revolutionary technology, in cancer management, and the issues with reimbursement of those technologies.

Cancer is a different kind of field than some others.

You have patients who reach a stage, for example, when they’re terminal and they have exhausted therapeutic options. Many oncologists are willing to look at a tumor and try to find a mutation that’s a driver mutation for which there’s a targeted therapy that may have been demonstrated to work in another tumor type, but has not yet been proved to work in the type of cancer the patient has. In the appropriate setting, they may be willing to offer it to a patient who has no other options.

They also may be able to offer the patient the opportunity to enroll in a clinical trial. But right now, I think the oncology community and payers need to come together to try to work out a paradigm that allows reimbursement for a test that provides useful information to a treating oncologist, that is, the tests that are request-

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ed by oncologists but haven’t yet reached the state of literature evidence that insurers are now requiring for reimbursement of most molecular tests.

In the oncology area, that will be critical going forward. The standard of care at major cancer institutes for some tumor types is to offer patients enrollment in clinical trials. Well, how do you find out if a patient is eligible for a trial that involves a targeted therapy?

You’ve got to do the mutation analysis. I don’t think the insurance industry is necessarily there yet in terms of understanding the need for, and appropriateness of, reimbursing testing for this purpose.

The FDA is concerned that they do not have knowledge of all the available tests that are already being performed in the labs across the United States.

Dr Pratt Right, because if the payer says it determines whether they’re going on the clinical trial, the clinical trial needs to pay for the test, not the insurance.

Many of those clinical trials are not covering the cost of the testing. Some are, some aren’t. It just depends.

Dr Klein Typically you would be testing the patients up front to see whether they are eligible, so it wouldn’t be in conjunction with any specific trial. Therefore, there is really nobody to pay for the test other than the patients themselves, because insurance often will not cover it. We’re also facing headwinds in pricing. We’ve had pretty significant reductions in reimbursement rates for molecular path testing over the past couple of years, basically because of some coding changes. I think the general headwinds with reimbursement we’re seeing across medicine are being felt in all specialties.

PMO What’s next for AMP in this process?

Dr Pratt AMP will continue to work with the FDA, CLIA, and other regulatory and reimbursement agencies on this issue. We are also having discussions with ASCO [American Society of Clinical Oncology], the AMA [American Medical Association], CAP, Palmetto, and other payers. AMP will continually work with these organizations, and we’re not going to stop, because patients are at the center of everything we do.

PMO Thank you very much for your time today.

This was very informative. We wish you success in providing the best resources for patients and the physicians who treat them. u

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Expanding Options for EGFR-Mutant Non–Small Cell Lung Cancer with Afatinib Elizabeth Tsui; Karen L. Reckamp, MD, MS City of Hope Comprehensive Cancer Center, Duarte, California

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argeted treatments have proved to be clinically successful and represent the realization of personalized medicine’s potential. In non–small cell lung cancer (NSCLC), molecularly targeted treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib have shown dramatic responses in Karen L. patients with activating mutations.1-3 Reckamp, MD, MS EGFR is a member of the human epidermal growth factor (HER) or ERBB family, a set of receptor tyrosine kinases that include EGFR (ERBB1), ERBB2, ERBB3, and ERBB4.4 The receptors and their ligands regulate the proliferation of cancerous cells. Elevated levels of EGFR and its ligands are found in early lung cancer and upon progression and metastasis.5 EGFR mutations occur in about 10% of patients with NSCLC but are commonly associated with female nonsmokers of Asian descent.1,6 These mutations occur within exons 18 to 21, which constitute most of the tyrosine kinase binding domain of the receptor.7,8 Exon 19 deletions (del19) and L858R within exon 21 are the 2 most common EGFR mutations, making up about 90% of all EGFR mutations. These mutations alter the receptor’s adeno­ sine triphosphate (ATP) binding pocket by improving its affinity for ATP, resulting in constitutive activa-

tion.4-8 Reversible EGFR TKIs, erlotinib and gefitinib, preferentially bind to the receptor’s ATP binding pocket, blocking ATP binding and the dimerization needed for receptor activation.4,6 In contrast, mutations such as exon 20 insertions and in-frame deletions or T790M alter the drug-receptor interaction and revert ATP binding affinity to that of a wild-type receptor.4-7 Despite the incredible responses observed in patients with activating EGFR mutations, resistance invariably occurs. Patients who respond to EGFR TKIs progress after a median of 12 months.9 After treatment with erlotinib or gefitinib, about 50% to 60% of patients develop the exon 20 resistance mutation, T790M.10 Other ways to acquire resistance include the development of mutations affecting downstream targets of EGFR. For example, mutations causing constitutive activation of PI3K lead to gefitinib resistance.11 To combat these resistance mechanisms, second- and third-generation EGFR TKIs have been developed. Second-generation HER TKIs covalently bind to the receptor’s activation domain and inhibit multiple members of the ERBB family.12-15 A recently approved drug that is a part of this class of TKIs is afatinib. Afatinib has primarily been evaluated in patients with EGFR mutation–positive NSCLC as firstline therapy and in those with acquired resistance. This review will present and examine the data from the use of afatinib for the treatment of patients with NSCLC.

Ms Tsui is a sophomore at Duke University majoring in biology and minoring in chemistry. She was selected as a CURE student for the City of Hope Eugene and Ruth Roberts 12-week Summer Student Academy where she performed research on EGFR mutations in lung cancer and their association with genetic susceptibility for cancer.

Dr Reckamp is Associate Professor in the Department of Medical Oncology and Therapeutics Research at City of Hope. She received her medical degree from the University of Chicago and her master’s degree in Clinical Investigation from UCLA. She completed residency training in Internal Medicine at Barnes-Jewish Hospital and a Hematology/Oncology fellowship at the David Geffen School of Medicine at UCLA. Her activities at City of Hope include Medical Director of the Thoracic Oncology program and Chair of the COHCCC scientific review committee. She is also a member of the NCCN Lung Cancer Guidelines Committee and a principal investigator for many phase 1 and 2 studies funded by the National Cancer Institute.

Preclinical and Phase 1 Results Afatinib is an aniline-quinazoline, irreversible EGFR/ HER2 inhibitor. In vitro assays demonstrated that afatinib and gefitinib have similar kinase inhibitory activity in fusion constructs with activating L858R mutations.14 In addition, when constructs were L858R/T790M double mutants, afatinib was more potent than gefitinib.

Compared against the HER2-specific inhibitors lapatinib and canertinib, afatinib showed similar inhibitory activity. Afatinib was also shown to specifically inhibit EGFR kinase activity when tested against 52 tyrosine and serine/threonine kinases. In human epidermal carcinoma cells (A431) expressing wild-type EGFR, murine NIH3T3 cells expressing wild-type HER2, breast cancer cells (BT-474), and gastric cancer cells (NCI-N87), afatinib inhibited EGFR or HER2 autophosphorylation at lower concentrations than lapatinib, canertinib, and gefi-

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tinib.14 Furthermore, afatinib concentrations needed to inhibit anchorage-independent colony formation of NIH-3T3 cells of 4 different isoforms (L858R/T790M, resistant exon 20 insertions, R108K-resistant mutations, or EGF-stimulated wild-type EGFR) were below concentrations needed for erlotinib’s inhibitory effect. In addition, growth factor–independent transformation of Ba/ F3 cells by EGFR expression was inhibited by afatinib at concentrations below corresponding erlotinib concentrations. Afatinib was also effective at inhibiting survival of erlotinib-sensitive cells (HCC827), erlotinib-resistant cells (NCI-1975), and wild-type cells (H1666). In xenograft models, EGFR phosphorylation and tumor volume decreased after 25 days of daily afatinib. In a murine L858R/T790M model, reduction in tumor volume was also shown with afatinib. In de novo L8585R/T790M tumor models, a daily dose of afatinib led to tumor reduction after 4 weeks. These studies suggested that afatinib may operate using a different mechanism to achieve EGFR inhibition, and it was hypothesized that it could provide clinical benefit where previous TKIs have failed.

A phase 1 trial enrolled 53 patients receiving escalating doses of afatinib from 10 to 50 mg daily. The study showed an adverse event (AE) profile similar to the previous generation of TKIs, with the most common AEs being rash and diarrhea.15 The majority of patients experienced grade 1 or 2 AEs, with no grade 4 or 5 AEs occurring. Eighty-three percent of patients experienced at least 1 drug-related AE. AEs included gastrointestinal (69.8%), skin (73.6%), and general disorders, eg, mucosal inflammation and fatigue (28.3%). Diarrhea was reported by 64.2% of patients, but it was generally well controlled with antidiarrheal medications. Rash was reported in 67.9% of patients, but dry skin, hand-foot syndrome, and acne were also reported. Pharmacokinetic studies showed that afatinib concentrations were dose proportional without correlation with clearance and body size or weight. Furthermore, at steady state, trough afatinib concentrations remained above afatinib’s effective concentrations in vitro.15 The results of these early studies prompted a series of large-scale clinical trials to test the toxicity and efficacy of afatinib in NSCLC (Table).

Phase 2/3 Clinical Trials The LUX-Lung 1 trial was a phase 2b/3 study that randomized 585 patients in a 2:1 ratio to afatinib (50 mg/ day) or placebo.16 Eligible patients had to have progressed on at least 12 weeks of erlotinib or gefitinib and at least 1 prior chemotherapy regimen. Retrospective analysis of tissue samples in only 24% of patients showed that 68% were EGFR mutation positive, with the majority (79%) harboring the 2 most common mutations,

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KEY POINTS EGFR TKIs are effective in patients with activating EGFR mutations such as L858R and exon 19 deletions, the 2 most common EGFR mutations ➤ Afatinib is an irreversible, pan-HER inhibitor that is part of the second generation of EGFR TKIs ➤ Afatinib has demonstrated improved progressionfree survival in patients with EGFR-activating mutations as first-line treatment when compared with chemotherapy ➤ Afatinib has not shown a clinical benefit for overall survival, and response rates are about 8% for patients with acquired resistance. ➤

L858R or del19. The primary end point was overall survival (OS), and progression-free survival (PFS), objective response rate (ORR), length of response, safety, and quality of life (QOL) were secondary end points. The primary analysis did not detect a significant difference in OS between treatment groups in the overall population (10.8 vs 12.0 months, afatinib vs placebo; P = .74) or between subgroups. When analyzed by mutation status, EGFR mutation–positive patients who received afatinib had increased PFS when compared with the EGFR mutation–positive patients who received placebo (median 3.3 vs 1.0 months; P = .009; hazard ratio [HR], 0.51). In

Afatinib has primarily been evaluated in patients with EGFR mutation–positive NSCLC as first-line therapy and in those with acquired resistance. contrast, no difference in PFS was seen in patients with less common mutations or in patients without activating EGFR mutations (median 2.8 vs 1.8 months; P = .22; HR, 0.61). Patients meeting Jackman and colleagues’ criteria for acquired resistance had a median PFS of 4.5 months on afatinib, and placebo patients had a PFS of 1.0 month.16,17 Objective responses in the afatinib arm were observed in 7% of patients by independent assessment, with responses lasting approximately 22 weeks.

The QOL assessment used cough, dyspnea, and pain ratings to determine drug-related symptom improvement using the lung cancer–specific QOL questionnaire from the European Organisation for Research and Treatment of Cancer (EORTC).16 Analysis of QOL ratings showed that afatinib patients had a significantly higher inci-

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Table Summary of the LUX-Lung Trials Population LUX-Lung 1

16

LUX-Lung 219

LUX-Lung 3

20

LUX-Lung 4

22

LUX-Lung 5

23

LUX-Lung 624

LUX-Lung 726

LUX-Lung 827

Mutation status

Not required

Prior chemotherapy

≤2 lines

Prior TKI

≥12 weeks

Mutation status

EGFR positive

Prior chemotherapy

≤1 line of chemotherapy

Prior TKI

None

Mutation status

EGFR positive

Prior chemotherapy

None

Prior TKI

None

Mutation status

Not required

Prior chemotherapy

≤2 regimens

Prior TKI

≥12 weeks

Mutation status

Not required

Prior chemotherapy

≥1 regimens

Prior TKI

Erlotinib/gefitinib, afatinib (part B)

Mutation status

EGFR-mutant positive

Prior chemotherapy

None

Prior TKI

None

Mutation status

L858R or del19

Prior chemotherapy

None

Prior TKI

None

Mutation status

Not required (squamous cell carcinoma)

Prior chemotherapy

1 regimen

Prior TKI

None

Study Treatment

Primary Outcome

Afatinib (50 mg/day) vs placebo

OS 10.8 vs 12.0 mo (HR 1.08; 95% CI, 0.86-1.35; P = .74)

Afatinib 50 mg/day vs afatinib 40 mg/day

61% ORR

Afatinib 40 mg/day vs carboplatin/pemetrexed

PFS 11.1 vs 6.9 mo (HR 0.58; 95% CI, 0.43-0.78; P = .001)

Afatinib 40 mg/day

8.2% ORR (95% CI, 2.7%-18.1%)

Afatinib 50 mg/day until disease progression (part A); afatinib 40 mg/day plus paclitaxel vs investigator’s choice chemotherapy (part B)

PFS 5.6 vs 2.8 mo (HR 0.60; 95% CI, 0.43-0.85; P = .003)

Afatinib 40 mg/day vs cisplatin/gemcitabine

PFS 11 vs 5.6 mo (HR 0.28; 95% CI, 0.20-0.39; P <.001)

Afatinib 40 mg/day vs gefitinib 250 mg/day

Study Ongoing

Afatinib 40 mg/day vs erlotinib 150 mg/day

Study Ongoing

Prior TKIs included erlotinib or gefitinib.

HR indicates hazard ratio; mo, months; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.

dence of improvements in NSCLC-related symptoms.

In the afatinib treatment arm, 46% reported improvements in cough, 51% improvements in dyspnea, and 50% improvements in pain compared with 25%, 36%, and 32% of patients in the placebo group, respectively.

The AE profile of afatinib consisted of diarrhea, rash/ acne, stomatitis, itchiness, nosebleeds, and loss of appetite, with diarrhea and rash occurring in the majority of patients (17% and 14% grade 3, respectively). One

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hundred fifty of 390 patients (38%) on the afatinib arm required dose reduction, the majority because of diarrhea and rash. Few patients (7.6%) discontinued treatment because of drug-related AEs, indicating that dose reduction or supportive medications may be sufficient to palliate these effects.

Preclinical models, phase 1 trials, and LUX-Lung 1 established a maximum tolerated dose of 55 mg daily and a standard dose of 50 mg per day; however, because of

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toxicity, many patients (40% in LUX-Lung 1) needed dose reductions to 40 mg/day.14-16,18 These studies also established afatinib’s AE profile and indicated that dose reduction may be enough to lessen the severity and/or the likelihood of AEs. Study patients for LUX-Lung 2 were EGFR mutation–positive, advanced-stage adenocarcinoma patients from Taiwan and the United States who had never been treated with EGFR TKIs and had completed no more than 1 chemotherapy regimen.19 All patients received afatinib and started at either 50 mg/day (99 patients) or 40 mg/day (30 patients). The primary end point of this study was the percentage of patients with confirmed objective responses according to RECIST by independent assessment. Secondary end points included percentage of patients with disease control, time to objective response, response duration, tumor shrinkage, PFS, and OS. Median treatment duration was 12 months, with a median follow-up time of 22 months.

Seventy-nine patients (61%) in the overall population had an objective response to afatinib. Notably, there was no advantage associated with treating patients with 50 mg or 40 mg of afatinib daily. Median response duration was 12.9 months, and 82% experienced disease control.

Median PFS was 10.1 months, and median OS for all patients was 24.8 months. Of patients on the 50-mg dose, 28% and 22% experienced grade 3 skin events or diarrhea, respectively, but dose reduction to 40 mg significantly reduced the occurrence of these high-grade symptoms. Serious AEs occurred in less than 15% of patients in the 50-mg treatment arm, and this percentage was halved in the 40-mg treatment arm.19 Within LUXLung 2, the majority of patients harbored 1 of 2 EGFR mutations, L858R or a del19. Of patients with the common mutations, 66% registered an objective response compared with 39% of patients in the less common mutation subgroup. Of patients with common EGFR mutations, 88% had disease control compared with 57% of patients with other mutations. This study was one of the first to provide results about how patients with less common mutations may respond to TKI treatment.

LUX-Lung 3 was the first global study comparing afatinib with the standard systemic chemotherapy (cisplatin/pemetrexed) and demonstrated afatinib’s superiority to chemotherapy in EGFR mutation–positive patients.20 Patients (N = 345) with activating EGFR mutations were randomized to afatinib 40 mg/day or up to 6 cycles of cisplatin/pemetrexed chemotherapy every 3 weeks.

Patients were treatment naive, and PFS was the primary end point. Secondary end points included ORR, disease control, safety, and AE profile. PFS for afatinib was 11.1 months compared with 6.9 months for cisplatin/pemetrexed (HR, 0.58; 95% CI, 0.43-0.78; P = .001). PFS for patients with common EGFR mutations was 13.6 months

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(HR, 0.47). Disease was well controlled in both treatment arms (90% with afatinib vs 81% with chemotherapy). Similar to LUX-Lung 1, cough and dyspnea symptoms were delayed with afatinib treatment (HR, 0.60; 95% CI, 0.41-0.87; P = .007 and HR, 0.68; 95% CI, 0.50-0.93; P = .015, respectively). More patients receiving afatinib reported improvements in shortness of breath (P <.001), and patients with baseline symptoms benefitted the most from afatinib treatment. Longitudinal analysis also showed that patients on afatinib had significantly better improvements in physical, role, and cognitive function.21 Overall, this was the largest study showing that afatinib could lead to significant benefits for patients with EGFR-mutant NSCLC as first-line therapy.

Overall, LUX-Lung 3 was the largest study showing that afatinib could lead to significant benefits for patients with EGFRmutant NSCLC as first-line therapy.

LUX-Lung 4 examined whether a daily 50-mg dose of afatinib could benefit patients who progressed on previous TKI treatment.22 The trial enrolled 62 patients with advanced-stage adenocarcinoma who had progressed after at least 12 weeks of erlotinib or gefitinib treatment (95.2% for at least 24.4 weeks), which served to enrich for those who developed resistance according to the Jackman criteria (82.3%).17 Seventy-two percent had an EGFR mutation in the primary tumor, and 2 patients (3.2%) developed a known T790M mutation in addition to the original activating mutation.22 Most patients discontinued treatment by the second analysis, with 64.5% discontinuing because of progression. A partial response was achieved by 8.2% of patients, 57.4% had stable disease for at least 6 weeks, and 65.6% achieved disease control. The average duration of response was 24.4 weeks, with afatinib reducing lesion size in 79% of patients.22 Median PFS was 4.4 months, and median OS was 18.4 months. There was no difference in outcomes observed when analyzing subgroups by sex, type of previous treatment, and number of chemotherapy regimens.

Treatment was discontinued in 29% of patients because of AEs. Given that previous response rates were 0% to 3%, this study showed that afatinib has a modest effect in patients with acquired resistance to EGFR TKI therapy following numerous prior treatments.

LUX-Lung 5 assessed the benefit of continued EGFR inhibition after progression on afatinib.23 Part A of the study enrolled 1154 patients with advanced-stage NSCLC who had received at least 1 chemotherapy regi-

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men and in whom erlotinib or gefitinib had failed; patients received a 50-mg daily dose of afatinib alone until disease progression. Patients who benefited from afatinib treatment could then be randomized to receive afatinib (40 mg/day) plus paclitaxel combination therapy or investigator’s choice chemotherapy in part B; 202 patients were randomized in a 2:1 ratio. Those who received afatinib plus paclitaxel had a significant improvement in median PFS over chemotherapy at 5.6 versus 2.8 months (HR, 0.60; 95% CI, 0.43-0.85; P = .003), but OS was similar in both arms. Toxicities were consistent with prior studies, and the most common AEs on the afatinib plus paclitaxel arm were diarrhea (53.8%), alopecia (32.6%), and asthenia (27.3%). This study verifies previous results that indicate afatinib’s clinical benefit in patients with EGFR-mutant NSCLC.

LUX-Lung 7 will help to assess afatinib compared with gefitinib to determine whether afatinib may improve PFS and OS over first-generation EGFR TKIs. LUX-Lung 6 randomized 364 treatment-naive, EGFR mutation–positive patients with late-stage adenocarcinoma to afatinib 40 mg/day versus cisplatin and gemcitabine every 3 weeks.24 Confirming previous results, the majority of patients had the 2 most common EGFR mutations, with only 2.5% of the study population harboring other mutations. The researchers’ primary aim was PFS, but QOL (assessed using the EORTC QOL questionnaire), ORR, disease control, and duration of response were also evaluated. PFS was improved in the afatinib treatment arm, except in patients with uncommon EGFR mutations or those who were former smokers. Median PFS was 11 months with afatinib compared with 5.6 months with chemotherapy (HR, 0.28; 95% CI, 0.20-0.39; P <.001). Sixty-six percent of patients experienced an objective response, and duration of response was 9.7 months with afatinib compared with 23% and 4.3 months, respectively, with chemotherapy. Length of disease control was also extended in the afatinib group (11.1 vs 5.7 months). For patient-reported outcomes, the afatinib group reported more improvements in cough, dyspnea, and general pain. Time to deterioration for these symptoms was also significantly longer in afatinib-treated patients. Grade 1/2 AEs were more likely in the afatinib treatment group (62.8% vs 38.9%). This and previous studies suggest that many of the less common EGFR mutations act as activating mutations; however, a subset may be associated with a decreased response to

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afatinib.18,24 This study confirmed the benefit of afatinib as initial therapy for patients with EGFR mutation–positive NSCLC. A recent pooled analysis of LUX-Lung 320 and LUXLung 624 was presented that included 709 patients randomized in both studies to evaluate OS in patients with exon 19 (n = 355) and exon 21 (n = 276) mutations.25 Although an improvement in PFS has been demonstrated with EGFR TKI therapy compared with chemotherapy in EGFR-mutant NSCLC for all agents investigated, an OS benefit had not previously been shown. This exploratory analysis did not show an improvement in OS with afatinib compared with chemotherapy at 25.8 versus 24.5 months (HR, 0.91; 95% CI, 0.75-1.11; P = .37) in the combined group. When separated by exon 19 versus exon 21 mutations, a survival benefit was seen specifically in those with del19 mutations (HR, 0.59; 95% CI, 0.45-0.77; P <.001). The combined analysis provides hypothesis-generating results but is limited by multiple testing with data from 2 separate trials with differing populations. A number of patients enrolled did not receive EGFR TKI therapy for EGFR-mutant NSCLC, which may influence the results, and these data were not available for the analysis. This study does suggest that EGFR-directed therapies may have differing outcomes based on the specific EGFR mutation.

Afatinib has yet to show how it differs from the previous generation of EGFR treatments. Both inhibit EGFR function and show benefits for PFS and ORR over chemotherapy, but resistance and variability of response within mutation type remain an issue. An ongoing trial, LUX-Lung 7, will help to assess afatinib compared with gefitinib to determine whether afatinib may improve PFS and OS over first-generation EGFR TKIs.26 LUX-Lung 8 is assessing afatinib versus erlotinib in patients with squamous cell carcinoma, although this population has demonstrated limited benefit with EGFR TKI therapy.27

Acquired Resistance Through its differential mechanism of irreversible binding, afatinib was thought to provide a potential benefit over reversible EGFR inhibitors to slow or even stop the development of T790M gatekeeper mutations, although this has not been demonstrated in a clinical setting. Like afatinib, dacomitinib is another irreversible pan-HER inhibitor that has shown promise in preclinical models. Unfortunately, this second-generation TKI has not established clinical efficacy against T790M.13,28 Benefits for those with acquired resistance are still minimal, and alternative therapeutic strategies are being explored.

Cell line studies have shown that higher doses of afatinib are needed to inhibit EGFR in resistant cells, so there is

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a possibility that an effective dose against T790M exceeds the maximum tolerated dose of 55 mg. To answer this need, combination treatment with afatinib and the EGFR monoclonal antibody cetuximab has been evaluated and led to clinical benefit.29 Studies in preclinical models of EGFR TKI resistance due to T790M demonstrated efficacy with the combination.30 A phase IB trial showed a promising response rate of 32% with an 8-month median duration of response in patients with EGFR-mutant lung cancer with EGFR TKI resistance.29 Genomic analysis of patient tumor samples found alteration in NF2 and TSC1, which modulate mTOR signaling as a potential pathway of resistance in this population.31 Third-generation, specific T790M inhibitors that target mutant EGFR and T790M, but largely spare wildtype receptors, also show early clinical efficacy in those who develop resistance due to the T790M mutation.32,33

Conclusion Targeted treatments have proved to be a major advancement in the fight against cancer. Patients with EGFR mutant–positive advanced-stage lung cancer who are treated with EGFR TKIs have a survival rate double what it was previously with chemotherapy alone. Adverse effects of afatinib are similar to those seen with the previous generation of inhibitors, and its approval supports the use of EGFR TKIs in this setting. While more is being done to further improve efficacy and combat resistance to EGFR TKIs, afatinib offers additional options for first-line therapy and is a step forward in the treatment of patients with EGFR-mutant NSCLC. u References

1. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129-2139.

2. Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497-1500.

3. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-957.

4. Pao W, Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer. 2010;10:760-774.

5. Veale D, Kerr N, Gibson GJ, et al. Characterization of epidermal growth factor receptor in primary human non-small cell lung cancer. Cancer Res. 1989;49:13131317.

6. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008; 359:1367-1380.

7. Wu JY, Yu CJ, Chang YC, et al. Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Cancer Res. 2011;17:3812-3821.

8. Ohashi K, Maruvka YE, Michor F, et al. Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J Clin Oncol. 2013;31:1070-1080.

9. Yu HA, Pao W. Targeted therapies: afatinib – new therapy option for EGFR-mutant lung cancer. Nat Rev Clin Oncol. 2013;10:551-552.

10. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:e73.

11. Engelman JA, Mukohara T, Zejnullahu K, et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer.

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J Clin Invest. 2006;116:2695-2706.

12. Mok T, Lee K, Tang M, et al. Dacomitinib for the treatment of advanced or metastatic non-small-cell lung cancer. Future Oncol. 2014;10:813-822.

13. Ramalingam SS, Blackhall F, Krzakowski M, et al. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2012;30:3337-3344.

14. Li D, Ambrogio L, Shimamura T, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene. 2008;27:47024711.

15. Yap TA, Vidal L, Adam J, et al. Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J Clin Oncol.

2010;28:3965-3972.

16. Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012;13:528-538.

17. Jackman D, Pao W, Riely GJ, et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol. 2010;28:357-360.

18. Marshall J, Hwang J, Eskens FA, et al. A phase I, open-label, dose escalation study of afatinib, in a 3-week-on/1-week-off schedule in patients with advanced solid tumors. Invest New Drugs. 2013;31:399-408.

19. Yang JC, Shih JY, Su WC, et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol. 2012;13:539-548.

20. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327-3334.

21. Yang JC, Hirsh V, Schuler M, et al. Symptom control and quality of life in LUXLung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3342-3350.

22. Katakami N, Atagi S, Goto K, et al. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013;31:3335-3341.

23. Schuler MH, Yang CH, Park K, et al. Continuation of afatinib beyond progression: results of a randomized, open-label, phase III trial of afatinib plus paclitaxel (P) versus investigator’s choice chemotherapy (CT) in patients (pts) with metastatic non-small cell lung cancer (NSCLC) progressed on erlotinib/gefitinib (E/G) and afatinib – LUX-Lung 5 (LL5). J Clin Oncol. 2014;32(suppl). Abstract 8019.

24. Wu YL, Zhou C, Hu CP, et al. Afatinib versus cisplatin plus gemcitabine for firstline treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15:213-222.

25. Yang JCH, Wu YL, Schuler M, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LuxLung 6): analysis of overall survival data from two randomised, phase 3 trials.

Lancet Oncol. 2015;16:141-151.

26. LUX-Lung 7: a phase IIb trial of afatinib (BIBW2992) versus gefitinib for the treatment of 1st line EGFR mutation positive adenocarcinoma of the lung. Clinical Trials.gov website. www.clinicaltrials.gov/ct2/show/NCT01466660. Published November 4, 2011. Updated July 9, 2014. Accessed July 18, 2014.

27. LUX-Lung 8: a phase III trial of afatinib (BIBW 2992) versus erlotinib for the treatment of squamous cell lung cancer after at least one prior platinum based chemotherapy. ClinicalTrials.gov website. www.clinicaltrials.gov/ct2/show/NCT01523587.

Published January 30, 2012. Updated July 9, 2014. Accessed July 18, 2014.

28. Reckamp KL, Giaccone G, Camidge DR, et al. A phase 2 trial of dacomitinib (PF-00299804), an oral, irreversible pan-HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non-small cell lung cancer after failure of prior chemotherapy and erlotinib. Cancer. 2014;120:1145-1154.

29. Janjigian YY, Smit EF, Groen HJ, et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov. 2014;4:1036-1045.

30. Regales L, Gong Y, Shen R, et al. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J Clin Invest.

2009;119:3000-3010.

31. Pirazzoli V, Nebhan C, Song X, et al. Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1. Cell Rep. 2014;7:999-1008.

32. Sequist LV, Soria JC, Gadgeel SM. First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M). J Clin Oncol. 2014;32(suppl). Abstract 8010.

33. Janne PA, Ramalingam SS, Yang JCH, et al. Clinical activity of the mutantselective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor–resistant non-small cell lung cancer (NSCLC). J Clin Oncol. 2014;32(suppl). Abstract 8009.

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ISTODAX® (romidepsin) for injection is indicated for treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.

This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

ISTODAX FOR THE 2ND-LINE TREATMENT OF PTCL

Important Safety Information WARNINGS AND PRECAUTIONS • Myelosuppression: ISTODAX® (romidepsin) can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; monitor blood counts regularly during treatment with ISTODAX; interrupt and/or modify the dose as necessary • Infections: Fatal and serious infections, including pneumonia, sepsis, and viral reactivation, including Epstein Barr and hepatitis B viruses, have been reported during and within 30 days after treatment with ISTODAX in clinical trials. The risk of life threatening infections may be greater in patients with a history of prior treatment with monoclonal antibodies directed against lymphocyte antigens and in patients with disease involvement of the bone marrow. Reactivation of Epstein Barr viral infection led to liver failure.

Consider monitoring for reactivation and antiviral prophylaxis in patients with evidence of prior hepatitis B infection. Ganciclovir prophylaxis failed to prevent Epstein Barr viral reactivation in one case • Electrocardiographic (ECG) changes: ECG changes have been observed with ISTODAX. In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, consider cardiovascular monitoring of ECGs at baseline and periodically during treatment. Confirm that potassium and magnesium levels are within the normal range before administration of ISTODAX • Tumor lysis syndrome: TLS (Tumor lysis syndrome) has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden are at greater risk and should be closely monitored and managed as appropriate • Embryo-fetal toxicity: ISTODAX may cause fetal harm when administered to a pregnant woman. Advise women of potential hazard to the fetus and to avoid pregnancy while receiving ISTODAX

ADVERSE REACTIONS Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (N=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (N=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/ fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%).

ISTODAX® is a registered trademark of Celgene Corporation. © 2014 Celgene Corporation 10/14 US-IST140021

www.istodax.com

ISTODAX demonstrated efficacy in PTCL after at least one prior therapy1 Efficacy and safety evaluated in the largest prospective single-arm PTCL study (Study 3, N=131) in a pretreated, histologically diverse PTCL population. All patients received prior systemic therapy for PTCL. Patients could be treated until disease progression at their discretion and that of the investigator.

60% (12/20) of complete responses were known to exceed

26% ORR

11.6 Months

(34/130)

(CR + CRu + PR) [95% CI: 18.8, 34.6a]

15% CR/CRu

(20/130)

Primary End Point

(CR + CRu) [95% CI: 9.7, 22.8a] 0

2

4

6

8

10

12

14

16

Months

• Follow-up on the remaining 8 patients was

56 days

(1.8 months, n=34)

median time to objective disease response2

discontinued prior to 8.5 months

a95% confidence interval. Response rates above are rounded to the nearest whole number.

CR=complete response; CRu=complete response unconfirmed; ORR=overall disease response rate.

Infections were the most common type of serious adverse event reported in Study 3 (N=131) and Study 4 (N=47).

In Study 3, 26 patients (20%) experienced a serious infection, including 6 patients (5%) with serious treatmentrelated infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections.

The most common adverse reactions regardless of causality in Study 3 (N=131) were nausea (59%), asthenia/ fatigue (55%), thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (N=47) were asthenia/fatigue (77%), nausea (75%), thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%).

DRUG INTERACTIONS • Monitor more frequently prothrombin time and International Normalized Ratio in patients concurrently administered ISTODAX and warfarin or coumarin derivatives • Romidepsin is metabolized by CYP3A4 —Monitor patients for toxicity related to increased romidepsin exposure and follow dose modifications for toxicity when ISTODAX is initially co-administered with strong CYP3A4 inhibitors —Avoid co-administration of ISTODAX (romidepsin) with rifampin and other potent inducers of CYP3A4 • Exercise caution with concomitant use of ISTODAX and P-glycoprotein (P-gp, ABCB1) inhibitors

USE IN SPECIFIC POPULATIONS • Pregnancy Category D: If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus • Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother • Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution Please see Brief Summary of Full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS, on the following pages.

References: 1. ISTODAX [package insert]. Summit, NJ: Celgene Corp; 2014.

2. Data on file, Celgene Corporation, Summit, NJ.

10-MG SINGLE-USE VIAL

T:7”

NK/T-cell lymphoma. In one case, ganciclovir prophylaxis failed to prevent Epstein Barr viral reactivation.

5.3 Electrocardiographic Changes Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies.

The clinical significance of these changes is unknown [see Adverse Reactions (6)].

In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, consider cardiovascular monitoring of ECGs at baseline and periodically during treatment.

Confirm that potassium and magnesium levels are within normal range before administration of ISTODAX [see Adverse Reactions (6)].

5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients with advanced stage disease and/or high tumor burden may be at greater risk, should be closely monitored, and managed as appropriate.

5.5 Use in Pregnancy There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose of 14 mg/m2/week. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS The following adverse reactions are described in more detail in other sections of the prescribing information.

• Myelosuppression [see Warnings and Precautions (5.1)] • Infection [see Warnings and Precautions (5.2)] • Electrocardiographic Changes [see Warnings and Precautions (5.3)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsor-conducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2.

The mean duration of treatment and number of cycles were 5.6 months and 6 cycles in Study 3 and 9.6 months and 8 cycles in Study 4.

Common Adverse Reactions Table 2 summarizes the most frequent adverse reactions (≥ 10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥ 10%) as adverse reactions are included in Table 2.

Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Adverse Reactions n (%) All grades Grade 3 or 4 All grades Grade 3 or 4 Any adverse reactions 128 (97) 88 (67) 47 (100) 40 (85) Gastrointestinal disorders Nausea 77 (59) 3 (2) 35 (75) 3 (6) Vomiting 51 (39) 6 (5) 19 (40) 4 (9) Diarrhea 47 (36) 3 (2) 17 (36) 1 (2) Constipation 39 (30) 1 (<1) 19 (40) 1 (2) Abdominal pain 18 (14) 3 (2) 6 (13) 1 (2) Stomatitis 14 (11) 0 3 (6) 0 General disorders and administration site conditions Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 8 (6) 22 (47) 8 (17) Chills 14 (11) 1 (<1) 8 (17) 0 Edema peripheral 13 (10) 1 (<1) 3 (6) 0 Blood and lymphatic system disorders Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36) Neutropenia 39 (30) 26 (20) 31 (66) 22 (47) Anemia 33 (25) 14 (11) 29 (62) 13 (28) Leukopenia 16 (12) 8 (6) 26 (55) 21 (45) (continued)

Cosmos Communications

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ISTODAX® (romidepsin) for injection For intravenous infusion only The following is a Brief Summary only; see full Prescribing Information for complete product information.

1 INDICATIONS AND USAGE ISTODAX is indicated for: • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.

These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day cycle.

Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the drug.

2.2 Dose Modification Nonhematologic toxicities except alopecia • Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2.

• Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2.

• Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction.

Hematologic toxicities • Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC ≥1.5×109/L and platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2.

• Grade 4 febrile (≥38.5°C) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤ Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2.

2.3 Instructions for Preparation and Intravenous Administration ISTODAX is a cytotoxic drug. Use appropriate handling procedures.

ISTODAX must be reconstituted with the supplied diluent and further diluted with 0.9% Sodium Chloride Injection, USP before intravenous infusion.

• Each 10 mg single-use vial of ISTODAX (romidepsin) must be reconstituted with 2 mL of the supplied diluent. With a suitable syringe, aseptically withdraw 2 mL from the supplied diluent vial, and slowly inject it into the ISTODAX (romidepsin) for injection vial. Swirl the contents of the vial until there are no visible particles in the resulting solution. The reconstituted solution will contain ISTODAX 5 mg/mL. The reconstituted ISTODAX solution is chemically stable for up to 8 hours at room temperature.

• Extract the appropriate amount of ISTODAX from the vials to deliver the desired dose, using proper aseptic technique. Before intravenous infusion, further dilute ISTODAX in 500 mL 0.9% Sodium Chloride Injection, USP. • Infuse over 4 hours.

The diluted solution is compatible with polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), polyethylene (PE) infusion bags as well as glass bottles, and is chemically stable for up to 24 hours when stored at room temperature.

However, it should be administered as soon after dilution as possible.

Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia. Monitor blood counts regularly during treatment with ISTODAX, and modify the dose as necessary [see Dosage and Administration (2.2) and Adverse Reactions (6)].

5.2 Infections Fatal and serious infections, including pneumonia, sepsis, and viral reactivation, including Epstein Barr and hepatitis B viruses have been reported in clinical trials with ISTODAX. These can occur during treatment and within 30 days after treatment. The risk of life threatening infections may be greater in patients with a history of prior treatment with monoclonal antibodies directed against lymphocyte antigens and in patients with disease involvement of the bone marrow [see Adverse Reactions (6)].

Reactivation of hepatitis B virus infection has occurred in 1% of PTCL patients in clinical trials in Western populations [see Adverse Reactions (6)]. In patients with evidence of prior hepatitis B infection, consider monitoring for reactivation, and consider antiviral prophylaxis.

Reactivation of Epstein Barr viral infection leading to liver failure has occurred in a trial of patients with relapsed or refractory extranodal

T:7”

Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Adverse Reactions n (%) All grades Grade 3 or 4 All grades Grade 3 or 4 Metabolism and nutrition disorders Anorexia 37 (28) 2 (2) 21 (45) 1 (2) Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervous system disorders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigations Weight decreased 14 (11) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0

Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 or Baxter Oncology GmbH Halle/Westfalen, Germany ISTODAX® is a registered trademark of Celgene Corporation © 2010-2014 Celgene Corporation. All Rights Reserved.

Pat.www.celgene.com/therapies IST_PTCL_BSv006 10/2014

Cosmos Communications

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QC

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Serious Adverse Reactions Infections were the most common type of SAE reported. In Study 3, 26 patients (20%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥ 2% of patients in Study 3 were pyrexia (8%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥ 2 patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%).

Reactivation of hepatitis B virus infection has occurred in 1% of patients with PTCL patients in clinical trials in Western population enrolled in Study 3 and Study 4 [see Warnings and Precautions (5.2)].

Deaths due to all causes within 30 days of the last dose of ISTODAX occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause.

Discontinuations Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥ 2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%).

6.2 Postmarketing Experience No additional safety signals have been observed from postmarketing experience.

7 DRUG INTERACTIONS 7.1 Warfarin or Coumarin Derivatives Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Although the interaction potential between ISTODAX and warfarin has not been formally studied, monitor PT and INR more frequently in patients concurrently receiving ISTODAX and warfarin.

7.2 Drugs That Inhibit Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Strong CYP3A4 inhibitors increase concentrations of romidepsin. In a pharmacokinetic drug interaction trial the strong CYP3A4 inhibitor ketoconazole increased romidepsin (AUC0-∞) by approximately 25%.

Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity [see Dosage and Administration (2.2)] when romidepsin is initially co-administered with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole).

7.3 Drugs That Induce Cytochrome P450 3A4 Enzymes Avoid co-administration of ISTODAX with rifampin.

In a pharmacokinetic drug interaction trial with co-administered rifampin (a strong CYP3A4 inducer), romidepsin exposure was increased by approximately 80% and 60% for AUC0-∞ and Cmax, respectively. Typically, co-administration of CYP3A4 inducers decrease concentrations of

drugs metabolized by CYP3A4. The increase in exposure seen after co-administration with rifampin is likely due to rifampin’s inhibition of an undetermined hepatic uptake process that is predominantly responsible for the disposition of ISTODAX. It is unknown if other potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) would alter the exposure of ISTODAX. Therefore, the use of other potent CYP3A4 inducers should be avoided when possible.

7.4 Drugs That Inhibit Drug Transport Systems Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.5)].

There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus.

Romidepsin was administered intravenously to rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption or post-implantation loss was observed at the high-dose of 0.5 mg/kg/day, a maternally toxic dose. Adverse embryo-fetal effects were noted at romidepsin doses of ≥0.1 mg/kg/day, with systemic exposures (AUC) ≥0.2% of the human exposure at the recommended dose of 14 mg/m2/week.

Drug-related fetal effects consisted of folded retina, rotated limbs, and incomplete sternal ossification.

8.3 Nursing Mothers It is not known whether romidepsin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of ISTODAX in pediatric patients has not been established.

8.5 Geriatric Use Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were >65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment No dedicated hepatic impairment study for ISTODAX has been conducted.

Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution.

8.7 Renal Impairment No dedicated renal impairment study for ISTODAX has been conducted.

Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution.

10 OVERDOSAGE No specific information is available on the treatment of overdosage of ISTODAX. Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heartbeat, staggering gait, tremor, and tonic convulsions.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required.

There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable.

BRAF MUTATIONS IN NSCLC

BRAF Mutations: An Old Oncogene and a New Target in Nonâ&#x20AC;&#x201C;Small Cell Lung Cancer Shihfan Yeh, MD; Lyudmila Bazhenova, MD University of California, San Diego, Moores Cancer Center San Diego, CA

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ung carcinoma has been the leading cause of cancer deaths in the United States and worldwide despite advances in chemotherapy.1,2 Management of nonâ&#x20AC;&#x201C;small cell lung cancer (NSCLC) has evolved significantly since 2004, when mutations in epidermal growth factor receptor (EGFR) were found to be the determining factor of response to geLyudmila Bazhenova, MD fitinib in a small subset of patients.3,4 This has led to the discovery of an increasing number of driver mutations over the past decade, allowing advancement in targeted and personalized therapy. For example, mutations in several other genes, including KRAS, ALK, HER2, BRAF, ROS1, PI3KCA, RET, and MET, were also found to be involved in carcinogenesis of NSCLC. Currently, only about a third of all NSCLCs are left without a known driver mutation.5 However, therapeutic approaches are still limited because of the lack of validated targeted therapies available for most of the abovementioned mutations.

The MAPK/ERK pathway is one of the most crucial pathways that cells utilize for growth and survival.

During normal MAPK/ERK signaling, the appropriate ligand arrives and binds to a tyrosine kinase receptor such as MET, EGFR, or HER2 located on the cell membrane. The activated receptors can phosphorylate the downstream target RAS, which upon activation can recruit RAF kinase to the cellular membrane to be further phosphorylated.6 Three RAF isoforms exist (ARAF, BRAF, and CRAF [Raf-1]), belonging to the family of

Dr Yeh received her medical degree from the National Cheng-Kung University, Taiwan, and is currently practicing as a second-year fellow in the Division of Hematology/Oncology at the University of California, San Diego (UCSD).

Dr Bazhenova is Associate Clinical Professor of Medicine in the Division of Hematology/Oncology and is Medical Director of the UCSD Moores Cancer Center Infusion Center. Her clinical practice and research concentrate on lung cancer, particularly as it relates to females and nonsmokers. She actively participates in cooperative group trials and takes an active role in designing and implementing clinical investigations, including phase 2 studies and correlative science projects with several UCSD investigators.

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serine/threonine protein kinases. Among the 3 RAF kinases, BRAF is the major signal transducer in the activation of MEK and ERK, as it displays the highest affinity for MEK1/2 (Figure).7 Activated BRAF phosphorylates downstream MEK, which in turn phosphorylates ERK, which can translocate into the nucleus and phosphorylate appropriate transcription factors responsible for cellular proliferation, differentiation, senescence, and apoptosis. Therefore, components of the MAPK/ERK pathway have been the targets of interest for cancer therapeutics.

A number of activating somatic BRAF mutations were first identified in various cancers in 2002, occurring in approximately 8% of all cancers and 3% of lung cancers.8,9 More than 50 missense mutations in the BRAF gene have been identified thus far, with the majority of them mapped to the kinase domain. Biochemical analysis of cells transfected with activating BRAF mutations shows an elevated level of phosphorylated ERK1/2.9 Mutations found outside the kinase domain can also increase BRAF activity by altering phosphorylation sites (S364, S428, and T439) on BRAF that are required for AKT-mediated inactivation.8-10 Improper inactivation leads to prolonged BRAF activation and thus can stimulate cell proliferation and transformation in the absence of RAS activation.

BRAF Mutations in Lung Cancer BRAF mutations have been identified in a variety of cancers, including approximately 50% of malignant melanoma and papillary thyroid cancer, and to a much lesser degree (<30%) in ovarian serous adenocarcinoma and colorectal cancer, and rarely (<5%) in non-Hodgkin lymphoma and NSCLC.11 The most common BRAF mutation is an amino acid substitution of valine to glutamate at residue 600 (V600E) in the activation segment of the kinase domain, causing BRAF to be constitutively active. V600E mutations account for almost all (>90%) of BRAF mutations in melanoma but only about half in NSCLC. Furthermore, BRAF mutations in NSCLC are much more diverse and show a wide spectrum of kinase activity compared with those found in melanoma.12 The role of BRAF in carcinogenesis has been demonstrated in vivo, where transgenic expression of BRAF V600E within lung tissues of mice results in the develop-

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ment of lung cancers with bronchioalveolar carcinoma features similar to those observed in humans.13 Consistent with the notion that continued BRAF activation is required for maintenance of the tumor, removal of the mutant transgene leads to dramatic tumor regression, as well as marked dephosphorylation of MEK1/2 and ERK1/2 and a decrease in cyclin D level.13 Importantly, in vivo pharmacologic inhibition of MAPK/ERK with a specific MEK inhibitor leads to tumor regression and increased apoptosis.13 Together, these findings support BRAF V600E as an oncogenic mutation and demonstrate the dependency of BRAF-mutant lung tumors on sustained activation of MAPK signaling.

The majority of BRAF mutations occur within exon 11 or 15. Some of the most common BRAF mutations are V600E and D594G (exon 15), and G469A (exon 11). Among the reported series, only 2 groups, Paik et al14 and Kinno et al,15 found a substantially higher percentage of the G469A mutation in NSCLC patients.

According to Paik et al,14 the G469A mutation may be related to a history of tobacco use. However, all patients included in their study were either current or former smokers.14 In fact, Kinno et al15 reported no such association in their study, in which only half of the patients with BRAF-mutated tumors had a history of smoking.

Molecular profiling studies have shown that activating mutations in BRAF, EGFR, HER2, and KRAS genes are generally nonoverlapping in NSCLC.16 However, in the case series reported, several rare cases of concomitant mutations have been described. Marchetti et al17 reported 2 tumors harboring concomitant BRAF V600E and EGFR mutations, and Kinno et al15 reported 5 tumors with concomitant non-V600E BRAF and EGFR mutations. In addition, Cardarella et al18 found 1 patient with a BRAF V600E mutation and concurrent PIK3CA mutation and 2 patients harboring activating G646 mutations and KRAS mutations concomitantly. Another 2 case series also found concomitant KRAS with BRAF mutation.15,19 The question of whether coexisting driver mutations exert the same oncogenicity remains unresolved, and it poses an extreme challenge in the selection of a treatment option that best suits the patient. In addition, coexistence of 2 mutations can result in the emergence of resistance clinically. For example, in the presence of oncogenic RAS, inhibition of BRAF V600E mutation increases dimerization between BRAF (nonV600E or wild-type [WT]) and CRAF, leading to further activation of MAPK/ERK signaling.20,21 Therefore, extended genotyping may be necessary prior to initiating selected targeted therapy.

Clinicopathologic Features Several authors have reported the incidence of BRAF-

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KEY POINTS BRAF is an oncogene that encodes a protein kinase involved in MAPK pathway signaling. When mutated, the BRAF oncogene is constitutively active and stimulates proliferation and cell survival ➤ BRAF mutations occur in 1% to 5% of NSCLC, with the most common mutation being activating V600E mutation ➤ Ongoing trials are investigating the clinical efficacy of BRAF inhibitors in V600-mutant NSCLC, with or without MEK or MET inhibitors. Studies are also under way to look for targeted therapy for non– V600-mutated NSCLC. ➤

Figure The MAPK/ERK Figure1.

ThePathyway MAPK/ERK

Pathyway

(A) Under normal condition, RAS activation provid

(A) Under normal conditions, RAS activation provides the anchor for dimerization of RAF proteins (ARAF, BRAF, and CRAF). The BRAF, The activated RAF dimer com activated RAFand dimerCRAF). complex then activates the downstream effector molecules MEK/ERK, resulting in expression of genes for cell MEK/ERK, resulting in expression of(indicated genes for ce proliferation and survival.

(B) Activating BRAF mutant by *) constitutively activates the MAPK/ERK pathway in the form of amutant monomer,(indicated without the need activated RAS. by of*)anconstitutively activates the RTK indicates receptor tyrosine kinase.

without the need of an activated RAS.

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Table 1 Cohorts of BRAF-Mutated Nonâ&#x20AC;&#x201C;Small Cell Lung Cancer

N, Tumor Subtype

Study

BRAF Mutations

BRAF V600E (% of BRAF Mutations)

Other BRAF Mutations Identified

Female:Male

History of Smoking

Year

Paik et al

687 ADC

3%

50%

G469A (39%) D594G (11%)

All: 0.8:1 V600E: 1.8:1

100%

2011

Marchetti et al17

739 ADC 307 SCC

ADC: 4.9% SCC: 0.3%

56.8%

D594G, L597R/ V/Q, V600L, K601E/N, W604R, G606A/V G466V, G469A/V

All: 2.6:1 V600E: 8.9:1

70% (100% in non-V600E mutant)

2011

Kobayashi et al22

581 NSCLC 381 ADC 143 SCC 57 other

0.86% (ADC: 1% SCC: 0.6%)

40%

D594G (40%)

All: 0.46:1 V600E: 1.8:1

80%

2011

Cardarella et al18

883 NSCLC

4%

50%

D594G/N, V600K/L, K601E, T599_V600insT, G464E/R/V, G466R/V, G469A/ del/V

NA

81%

2013

Brustugun et al19

646 ADC 231 SCC

1.7% (ADC: Only tested 2.3% SCC: for V600E/K 0%)

2.1:1

71%

2014

Kinno et al15

2001 NSCLC 1835 ADC 160 SCC 6 others

1.3% (ADC: 29% 1.3% SCC: 0.6% )

54%

2014

14

G469A (21%) 1.14:1 K601E (14%) D594G/N, T599_ V600insT, G606R, G464E/R/V, S467L, G596R, A598T

ADC indicates adenocarcinoma; NA, not available; NSCLC, nonâ&#x20AC;&#x201C;small cell lung cancer; SCC, squamous cell carcinoma.

mutation in different histologic subsets (Table 1). Clinically, the incidence of BRAF mutations is lower in the Asian population (approximately 1%) when compared with the Caucasian population.15,22 The vast majority of BRAF mutations occur in adenocarcinoma and very rarely in squamous cell carcinoma. There is a probable slight female predilection for all BRAF mutations in NSCLC (Table 1), with an average female to male ratio of 2 to 1 for the V600E mutation,14,19,22 with the exception of 1 Italian study that reported a dramatically higher female predilection for V600E mutations, with a female-to-male ratio of 9 to 1.17 It is unlikely that ethnic differences account for the variation, because 3 other studies have reported similar findings with distinct patient populations from the United States, Norway, and Japan.14,19,22 One possibility is that there are significant differences in patient characteristics between the Italian group and the others. For instance, a patient population

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that is dominated by female smokers or females with advanced-stage cancer is likely to result in a higher female-to-male ratio because BRAF V600E mutation correlates with smoking history and possibly more aggressive disease. However, current published results are presented in cohorts, which mask potential differences of patient characteristics across studies.

In contrast to EGFR mutations, BRAF mutations are commonly associated with smoking status (54%-100% of patients with BRAF mutations are current or former smokers).14,15,17-19 Interestingly, it was noted in one report that all non-V600E mutations were found in smokers, whereas V600E mutations occurred more commonly in never-smokers (5% in never-smoker vs 2% in current or former smokers).17 However, the proportion of nonsmokers and/or light smokers did not differ significantly according to the types of BRAF mutations in other case series.15,18

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In papillary thyroid cancer, the BRAF V600E mutation is closely related to high-risk clinicopathologic factors such as extrathyroidal invasion, lymph node metastasis, and advanced TNM stage, as well as poorer outcome as evidenced by recurrent and persistent disease.23 The BRAF V600E mutation has also been described as an absolute risk factor for survival in colorectal cancer and melanoma.24 Whether the BRAF mutations carry any prognostic value in NSCLC remain unclear.

Currently, BRAF WT and BRAF-mutant NSCLC do not show a difference in overall survival (OS). Because of conflicting results, it is not clear whether the BRAF V600E mutation correlates with poor survival. For example, Marchetti et al17 reported a more aggressive pathology characterized by micropapillary features in V600E-mutated tumors as well as shorter disease-free survival and OS compared with BRAF WT. Cardarella et al18 found a lower response rate and a shorter progression-free survival to platinum-based chemotherapy in BRAF V600E-mutated populations when compared with patients with no V600E mutations; however, this did not reach statistical significance. Conversely, Brustugun et al19 reported no significant difference in OS between BRAF V600E/K and WT populations. Furthermore, a similar finding was described by Kinno et al15 when comparing OS across WT, V600E and non-V600E BRAF populations.

From a pathology standpoint, Yousem et al25 reported a correlation between BRAF V600E mutation and poorer prognosis in lung adenocarcinomas by noting a high prevalence of papillary growth in BRAF V600E cases, which has been associated with a more aggressive clinical course and higher pathologic stage. Immunohistochemical staining of NSCLC tissue samples from 5 patients with BRAF mutations (2 with a V600E mutation, 2 with a D594G mutation, and 1 with a silent mutation) showed higher Ki-67 antigen in 4 of 5 patients, which is also suggestive of higher-grade tumors.22

Therapies for BRAF-Mutated Lung Cancer At present, there is no FDA-approved treatment for BRAF-mutated NSCLC; however, the National Comprehensive Cancer Network (NCCN) guideline recommends vemurafenib or dabrafenib based on promising clinical data.

Current second-generation BRAF inhibitors, such as vemurafenib and dabrafenib, have been tailored to target the nearly universal BRAF V600 mutation in melanoma.

It has potent activity against the V600-mutated BRAF kinases regardless of the type of cancers. There are 2 case reports of patients with BRAF V600E lung adenocarcinoma who responded to vemurafenib26,27 and 1 for da足 brafenib.28 Dabrafenib received FDA Breakthrough

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Therapy Designation for BRAF V600E-mutated NSCLC based on interim analysis from an ongoing phase 2 trial (NCT01336634) published in 2013.29 In that report, 17 patients with BRAF V600E-mutated stage IV NSCLC in whom at least 1 prior line of platinum-containing chemotherapy had failed were given dabrafenib 150 mg orally twice daily. The overall response rate (ORR) and overall disease control rate were 54% and 61%, respectively. The response seemed durable in 2 patients who achieved a partial response and who had received treatment for over a year at the time of the report. This study is ongoing, with the primary outcome being ORR of single-agent dabrafenib versus combination therapy with the MEK inhibitor trametinib.

BRAF mutations are commonly associated with smoking status (54%-100% of patients with BRAF mutations are current or former smokers).

Despite the success with treatment for BRAF V600 mutations, preclinical data have shown that these selective BRAF inhibitors targeting specific V600 mutations do not display the same antiproliferative effect on lung cancer cell lines harboring activating non-V600 mutations.30 Currently, there is no established treatment for BRAF non-V600 mutations, and there is no evidence in the literature of successful treatment of non-V600 mutations using dabrafenib or vemurafenib. Future design of therapeutics for BRAF V600 and non-V600 mutants now focuses on the molecular components within the Ras-Raf-MEK-ERK pathway, including MEK, CRAF, and MET. Several studies have reported promising results from treating cancers requiring BRAF-dependent activation of the MAPK/ERK pathway.13,16,31-33 Analysis of BRAF V600E-mutated human cell lines, regardless of tissue lineage, has demonstrated a MEK dependency for growth.31 In addition, pharmacologic inhibition of the MEK signaling pathway leads to complete suppression of tumor growth in a mice xenograft.31 Treatment with MEK inhibitors has been demonstrated to induce pronounced tumor regression in lung cancer mouse models bearing tumors with the BRAF V600E mutation.13 Furthermore, NSCLC cell lines with either V600E or nonV600E BRAF mutations were found to be selectively sensitive to MEK inhibition compared with those harboring mutations in EGFR, RAS, or ALK, and ROS kinase fusions as demonstrated by decreased expression of phosphorylated ERK after exposure to a MEK inhibitor.16 Currently, MEK inhibitors are being studied in

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Table 2 Ongoing Therapeutic Trials for BRAF-Mutated Non–Small Cell Lung Cancer Drugs

Class

Design

Phase

Reference

Dabrafenib

BRAF inhibitor

With or without trametinib in pretreated stage IV NSCLC with 2 BRAF V600E mutation

NCT01336634

Vemurafenib

BRAF inhibitor

BRAF V600 mutated solid tumors and myeloma

2

NCRN396

Combination with sorafenib or crizotinib in BRAF-mutated cancers relapsed/refractory to standard therapy

1

NCT01531361

Vemurafenib ± sorafenib or crizotinib LGX818

BRAF inhibitor

Combination with MEK162 (MEK inhibitor) ± LEE011 (cyclin-dependent kinase inhibitor) in BRAF V600 mutated solid tumors

1b/2

NCT01543698

PLX8394

BRAF inhibitor

Single agent in BRAF-mutated melanoma, solid tumors, or hairy cell leukemia

1/2a

NCT02012231

PLX3603

BRAF inhibitor

Single agent in advance solid tumors with BRAF V600 mutation

1

NCT01143753

RAF265

Dual BRAF/ Combination with MEK162 in advanced solid tumors with VEGFR2 inhibitor BRAF V600E, NRAS, or KRAS mutations

1

NCT01352273

Selumetinib

MEK inhibitor

Single agent for unresectable or metastastic solid tumors with activating BRAF mutations

2

NCT00888134

Trametinib

MEK inhibitor

Randomized to trametenib or docetaxel as second-line therapy in stage IV NSCLC with KRAS, NRAS, BRAF, or MEK mutations

2

NCT01362296

Dasatinib

Multikinase inhibitor

Single agent in advanced NSCLC harboring a discoidin domain 2 receptor 2 or inactivating BRAF mutation

NCT01514864

Onartuzumab

MET inhibitor

Combination with vemurafenib and/or cobimetinib (MEK inhibitor) in BRAF V600 mutated, advanced, or metastatic solid tumors or KRAS-mutated stage IV colorectal carcinoma and NSCLC

NCT01974258

1

NSCLC indicates non–small cell lung cancer; VEGFR2, vascular endothelial growth factor receptor 2.

phase 2 trials as single agents or in combination with BRAF inhibitors (NCT01336634, NCT01362296, NCT00888134, NCT01974258; Table 2). Secondary resistance to BRAF inhibitors inevitably occurs in BRAF V600-mutated cancer, and most of the resistance mechanisms are upstream of MEK and therefore rely on MEK activity.34 It has also been shown that BRAF amplification contributes to resistance of BRAF V600-mutated colorectal cell lines to MEK inhibitors, and that combined MEK and BRAF inhibition was able to overcome resistance to either inhibitor alone.35 Because of the additive benefit of MEK inhibitors to enhance tumor inhibition and delay acquiring secondary resistance, combination therapy with BRAF inhibitors and MEK inhibitors is currently being studied and could become the trend in the future for the treatment of NSCLC with BRAF V600 mutations.

MET belongs to the family of membrane receptor ty-

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rosine kinases. Activation of MET can turn on a number of oncogenic pathways, including the Ras-Raf-MEKERK pathway. It has been shown in vitro that innate resistance to BRAF inhibitors is elicited by stromal cells in the tumor microenvironment via hepatocyte growth factor (HGF) secretion and subsequent MET activation, and that dual inhibition of RAF plus HGF or MET resulted in reversal of drug resistance.36 Pharmacologic inhibition of MET can be achieved using onartuzumab, a humanized monovalent monoclonal antibody directed against the extracellular domain of MET, thereby preventing the binding of its ligand, HGF. Currently, the MET inhibitor is being investigated in combination with a BRAF inhibitor, a MEK inhibitor, or both (NCT01974258).

Cyclin-dependent kinases (CDKs) belong to an important family of protein kinases that regulate critical cellular processes such as cell cycle, transcription, and

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mRNA processing. The development of a class of highly specific and orally bioavailable inhibitors of CDK4/6 has shown promising preclinical results when used in combination with other targeted therapies. By inhibiting the activation of CDK4/6, these drugs suppress the growth of tumor cells by blocking CDK-dependent phosphorylation of retinoblastoma protein, which leads to cell cycle arrest. When combined with LGX818 (a BRAF V600E inhibitor), LEE001 (a CDK inhibitor) has shown antitumor activity in melanoma models harboring activating BRAF mutations, even in melanoma models that are resistant to LGX818.37 The synergistic effect can be explained by CDK also working as a common downstream effector molecule of the MAPK/ERK signaling pathway.

Currently, the CDK inhibitor is being studied as part of a triple therapy with a BRAF and MEK inhibitor (NCT01543698).

Dasatinib is a multikinase inhibitor most commonly used in hematologic malignancies to target the BCRABL fusion protein. It was initially designed in a clinical trial38 to be used as first-line treatment for metastatic NSCLC for its Src family kinases (SFKs) inhibition property because elevated levels of activated SFKs are commonly seen in NSCLC39,40 and because SFKs play an important role in multiple processes, including angiogenesis, invasion, proliferation, and survival of cancer cells.41 The results from this clinical trial showed that the overall disease control rate was not superior to the historical response to standard chemotherapy. However, for the single patient who had a partial response after 12 weeks of treatment, the response was durable, and he had no evidence of disease 4 years after treatment.38 Subsequently, the patient’s tumor tissue was analyzed, and a kinase-inactivating BRAF mutation (BRAF Y472C) was found.42 Inactivating BRAF mutations has been demonstrated to activate the MAPK/ERK signaling pathway by activation of CRAF via heterodimerization.12,32,43 Sen et al42 discovered that dasatinib selectively induces irreversible senescence and cell cycle arrest in NSCLC bearing kinase-inactivating BRAF mutations. Although the precise mechanism of dasatinib-induced senescence and apoptosis in NSCLC remains unknown, current data support a role of BRAF-CRAF heterodimerization in sensitivity to dasatinib. A clinical trial targeting kinase-inactivating BRAF-mutant NSCLC (NCT­ 01514864) is under way.

Both vemurafenib and dabrafenib, as single agents, have shown high efficacy to inhibit MEK activity caused by the highly active BRAF V600E mutation. However, the MAPK/ERK signaling pathway can be activated by alternate pathways despite drug-mediated inhibition of activating BRAF mutants, resulting in secondary drug resistance. The knowledge of acquired resistance to

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BRAF V600 inhibitors comes largely from studies in melanoma. Multiple secondary resistance mechanisms have been described, and they can be separated as either ERK dependent or non-ERK dependent.34,44 ERK-dependent mechanisms are much more common and are usually associated with reactivation of the MAPK pathway via alternate pathways or upregulation of the signaling components in the MAPK pathway. Some of the ERK-dependent mechanisms include BRAF amplification or introduction of splice variants, upregulation of receptor tyrosine kinases, and acquired mutation in RAS.28,34,44 A number of therapies are being investigated to overcome secondary resistance, including combining BRAF V600 inhibitors with MEK and ERK inhibitors (Table 2).45,46

BRAF mutations have been identified in various cancers and are considered to be the driver mutations for approximately 1% to ~5% of NSCLCs. Paradoxical activation of the MAPK/ERK pathway on treatment with BRAF V600 inhibitors is well described.20,21 It has been shown in multiple systems, including human melanoma cell lines and tumor xenografts, that in the presence of oncogenic RAS mutations, BRAF V600E inhibitors lead to activation of CRAF by increasing WT and kinase-inactivating BRAF binding to CRAF to form heterodimers, which result in potentiated MAPK/ERK signaling. A new generation of RAF inhibitors called “paradox breakers,” including PLX8394 (NCT02012231) and PLX7904, are in development.

The paradox breakers do not elicit paradoxical activation and therefore potentially reduce the side effects of secondary cutaneous malignancies. In addition, they have also been shown to have inhibitory effects in vem­ urafenib-resistant melanoma cells with mutated RAS47 or BRAF V600E splice variants.48

Conclusion BRAF mutations have been identified in various cancers and are considered to be the driver mutations for approximately 1% to 5% of NSCLCs. The most common mutation reported is the activating BRAF V600E mutation. In contrast to melanoma, of which almost all result from BRAF V600E mutation, NSCLCs harbor a variety of BRAF mutations, some of which are kinase inactivating but still capable of activating the MAPK/ ERK pathway through transactivation of CRAF. BRAF mutations are more commonly found in patients with a history of smoking, and there may be a slight female

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predominance. Although some studies describe a correlation between BRAF V600E mutations with more aggressive pathologic features, the question of whether BRAF mutations carry any prognostic value is still up for debate. Currently, there is no FDA-approved treatment for BRAF-mutated NSCLC; however, BRAF V600 inhibitors are recommended by the NCCN guideline for patients with tumors harboring sensitive BRAF mutations. Investigation of combination therapies is under way to achieve a better response to therapy and to overcome secondary resistance. u

References

1. Bray F, Ren JS, Masuyer E, et al. Estimates of global cancer prevalence for 27 sites in the adult population in 2008. Int J Cancer. 2013;132:1133-1145.

2. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin. 2014;64: 9-29.

3. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129-2139.

4. Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497-1500.

5. Cheng L, Alexander RE, Maclennan GT, et al. Molecular pathology of lung cancer: key to personalized medicine. Mod Pathol. 2012;25:347-369.

6. Garnett MJ, Marais R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell. 2004;6:313-319.

7. Papin C, Denouel-Galy A, Laugier D, et al. Modulation of kinase activity and oncogenic properties by alternative splicing reveals a novel regulatory mechanism for B-Raf. J Biol Chem. 1998;273:24939-24947.

8. Brose MS, Volpe P, Feldman M, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 2002;62:6997-7000.

9. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer.

Nature. 2002;417:949-954.

10. Guan KL, Figueroa C, Brtva TR, et al. Negative regulation of the serine/threonine kinase B-Raf by Akt. J Biol Chem. 2000;275:27354-27359.

11. Machnicki MM, Stoklosa T. BRAF—a new player in hematological neoplasms.

Blood Cells Mol Dis. 2014;53:77-83.

12. Wan PT, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116:855-867.

13. Ji H, Wang Z, Perera SA, et al. Mutations in BRAF and KRAS converge on activation of the mitogen-activated protein kinase pathway in lung cancer mouse models. Cancer Res. 2007;67:4933-4939.

14. Paik PK, Arcila ME, Fara M, et al. Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol. 2011;29:2046-2051.

15. Kinno T, Tsuta K, Shiraishi K, et al. Clinicopathological features of nonsmall cell lung carcinomas with BRAF mutations. Ann Oncol. 2014;25:138-142.

16. Pratilas CA, Hanrahan AJ, Halilovic E, et al. Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res. 2008;68:9375-9383.

17. Marchetti A, Felicioni L, Malatesta S, et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol.

2011;29:3574-3579.

18. Cardarella S, Ogino A, Nishino M, et al. Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. Clin Cancer Res. 2013;19:4532-4540.

19. Brustugun OT, Khattak AM, Trømborg AK, et al. BRAF-mutations in non-small cell lung cancer. Lung Cancer. 2014;84:36-38.

20. Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140:209-221.

21. Hatzivassiliou G, Song K, Yen I, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464:431-435.

22. Kobayashi M, Sonobe M, Takahashi T, et al. Clinical significance of BRAF gene

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mutations in patients with non-small cell lung cancer. Anticancer Res. 2011;31:46194623.

23. Kim TH, Park YJ, Lim JA, et al. The association of the BRAF (V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis. Cancer. 2012;118:1764-1773.

24. Safaee Ardekani G, Jafarnejad SM, Tan L, et al. The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis.

PLoS One. 2012;7:e47054.

25. Yousem SA, Nikiforova M, Nikiforov Y. The histopathology of BRAF-V600E-mutated lung adenocarcinoma. Am J Surg Pathol. 2008;32:1317-1321.

26. Gautschi O, Pauli C, Strobel K, et al. A patient with BRAF V600E lung adenocarcinoma responding to vemurafenib. J Thorac Oncol. 2012;7:e23-e24.

27. Peters S, Michielin O, Zimmermann S. Dramatic response induced by vemurafenib in a BRAF V600E-mutated lung adenocarcinoma. J Clin Oncol.

2013;31:e341-e344.

28. Rudin CM, Hong K, Streit M. Molecular characterization of acquired resistance to the BRAF inhibitor dabrafenib in a patient with BRAF-mutant non-small-cell lung cancer. J Thorac Oncol. 2013;8:e41-e42.

29. Planchard D, Mazieres J, Riely GJ, et al. Interim results of phase II study BRF113928 of dabrafenib in BRAF V600E mutation-positive non-small cell lung cancer (NSCLC) patients. J Clin Oncol. 2013;31(suppl). Abstract 8009.

30. Yang H, Higgins B, Kolinsky K, et al. RG7204 (PLX4032), a selective BRAF V600E inhibitor, displays potent antitumor activity in preclinical melanoma models.

Cancer Res. 2010;70:5518-5527.

31. Solit DB, Garraway LA, Pratilas CA, et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature. 2006;439:358-362.

32. Smalley KS, Xiao M, Villanueva J, et al. CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations. Oncogene. 2009;28:85-94.

33. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107-114.

34. Wellbrock C. MAPK pathway inhibition in melanoma: resistance three ways.

Biochem Soc Trans. 2014;42:727-732.

35. Corcoran RB, Dias-Santagata D, Bergethon K, et al. BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci Signal. 2010;3:ra84.

36. Straussman R, Morikawa T, Shee K, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012;487:500-504.

37. Kim S, Loo A, Chopra R, et al. LEE011: an orally bioavailable, selective small molecule inhibitor of CDK4/6 – reactivating Rb in cancer. Mol Cancer Ther.

2013;12(11 suppl). Abstract PR02.

38. Johnson FM, Bekele BN, Feng L, et al. Phase II study of dasatinib in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:4609-4615.

39. Masaki T, Igarashi K, Tokuda M, et al. pp60c-src activation in lung adenocarcinoma. Eur J Cancer. 2003;39:1447-1455.

40. Zhang J, Kalyankrishna S, Wislez M, et al. SRC-family kinases are activated in non-small cell lung cancer and promote the survival of epidermal growth factor receptor-dependent cell lines. Am J Pathol. 2007;170:366-376.

41. Kim LC, Song L, Haura EB. Src kinases as therapeutic targets for cancer. Nat Rev Clin Oncol. 2009;6:587-595.

42. Sen B, Peng S, Tang X, et al. Kinase-impaired BRAF mutations in lung cancer confer sensitivity to dasatinib. Sci Transl Med. 2012;4:136ra70.

43. Garnett MJ, Rana S, Paterson H, et al. Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Mol Cell.

2005;20:963-969.

44. Sullivan RJ, Flaherty KT. Resistance to BRAF-targeted therapy in melanoma. Eur J Cancer. 2013;49:1297-1304.

45. Morris EJ, Jha S, Restaino CR, et al. Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov.

2013;3:742-750.

46. Hatzivassiliou G, Liu B, O’Brien C, et al. ERK inhibition overcomes acquired resistance to MEK inhibitors. Mol Cancer Ther. 2012;11:1143-1154.

47. Le K, Blomain ES, Rodeck U, et al. Selective RAF inhibitor impairs ERK1/2 phosphorylation and growth in mutant NRAS, vemurafenib-resistant melanoma cells. Pigment Cell Melanoma Res. 2013;26:509-517.

48. Basile KJ, Le K, Hartsough EJ, et al. Inhibition of mutant BRAF splice variant signaling by next-generation, selective RAF inhibitors. Pigment Cell Melanoma Res. 2014;27:479-484.

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RET ONCOGENE IN NSCLC

The RET Oncogene in Non–Small Cell Lung Cancer: Review of the Current Literature and Directions for the Future Rebecca A. Shatsky, MD; Lyudmila Bazhenova, MD University of California, San Diego, Moores Cancer Center San Diego, CA

D

espite recent advances, lung cancer remains the leading cause of cancerrelated death worldwide.1 In the past decade, the treatment of non–small cell lung cancer (NSCLC), which was once a disease with exceedingly few treatment options and historically poor outcomes, has begun to transform. The discovery of targetable cancer-drivRebecca A. ing mutations has added a promising new diShatsky, MD mension to the field, which was once confined to the use of cytotoxic agents that often induced minimal responses that were frequently short-lived. The discovery of the EML4 fusion gene and the success of the ALK mutant–targeting tyrosine kinase inhibitor (TKI) crizotinib has proved that these mutations can have serious clinical impact, and that design of new drugs targeting the mutations can potentially save many lives.2 Lyudmila Importantly, the oncogenic driver mutaBazhenova, MD tions in lung adenocarcinoma are generally mutually exclusive, so the discovery of each new oncogenic driver mutation may be helpful to a population of patients who previously were not eligible for available targeted lung cancer therapies.3-6 The list of identifiable drug targetable genetic mutations in lung cancer is growing fast, and one of the newer targets that is just beginning to be explored in human clinical trials is the RET proto-oncogene.

Dr Shatsky is an Oncology Fellow in the Division of Hematology/ Oncology, Department of Medicine at the University of California, San Diego (UCSD).

Dr Bazhenova is Associate Clinical Professor of Medicine in the Division of Hematology/Oncology and is Medical Director of the UCSD Moores Cancer Center Infusion Center. Her clinical practice and research concentrate on lung cancer, particularly as it relates to females and nonsmokers. She actively participates in cooperative group trials and takes an active role in designing and implementing clinical investigations, including phase 2 studies and correlative science projects with several UCSD investigators.

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Biology of the Native RET Oncogene The RET oncogene, located in the pericentromeric region of chromosome 10q11.2, was first identified and mapped in 1985 using cells transfected with human lymphoma DNA.7 RET was first identified as a receptor for the glial cell–derived neurotropic factor family of ligands, which are important for neuron signaling.8,9 RET is expressed at its highest levels during embryogenesis and has been implicated in the process of nephrogenesis, neural crest migration, as well as the maintenance of normal neuron function. RET expression decreases to much lower levels in healthy adult tissues but is still routinely expressed in neurons, parasympathetic ganglia, thyroid C cells, urogenital tract cells, and testis germ cells.10-14 Like many oncogenes, RET encodes a receptor tyrosine kinase (RTK). The RET RTK transmembrane receptor consists of 4 cadherin-like domains in its extracellular region, a calcium binding site, a transmembrane region, and an intracellular region containing the active tyrosine kinase domain.15,16 Upon binding of its ligand and coreceptor, RET autophosphorylates and in turn activates multiple downstream targets, including the RAS-MAPK-ERK1/2 and the PI3K/AKT signaling pathway.17 This leads to activation of multiple essential cell cycle activities, including signaling to induce proliferation and to promote cell survival.18 Oncogenic RET Gene There have been multiple previously identified mutations to the RET gene implicated in cancer development. For example, germline gain-of-function mutations in RET have long been implicated in the development of multiple endocrine neoplasia, which consists of medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism.19 In addition, many irradiation-induced papillary thyroid cancers contain RET gene rearrangements.20 It is estimated that RET mutations can be found in 30% to 50% of both medullary and papillary thyroid cancers.21,22 Further, germline loss-of-function mutations are now known to be responsible for Hirschsprung disease, a congenital abnormality in which neuroblasts in

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the developing gut fail to migrate and neural cells do not mature in the gastrointestinal tract, resulting in chronic constipation.23,24 In lung cancer, in a mechanism very similar to that of ALK gene rearrangements, or ROS1, a somatic gainof-function mutation in RET is responsible for creating a chimeric fusion oncogene, which can then lead to malignant transformation. When the intracellular kinase encoding domain of RET is fused to one of several recently identified gene partners, a fusion gene is created that encodes a constitutively active RTK. In 2011, Ju et al reported the first identified case of adenocarcinoma of the lung containing the RET fusion RTK, RET-KIF5B, in a 33-year-old nonsmoking patient.25 In 2012, several groups independently corroborated these results, identifying multiple different RET gene rearrangements and RET fusion proteins that are expressed at high levels in certain lung adenocarcinomas.6,25-28 The most frequent rearrangement is the fusion of RET to kinesin family member 5B (KIF5B), which is created by a pericentric inversion of chromosome 10.26 This particular gene fusion appears to be unique to adenocarcinoma of the lung. However, to date, 5 fusion partners of RET have been identified in NSCLC, including KIF5B-RET, CCDC6-RET, NCO4-RET, TRIM33RET, and, most recently, RUFY2-RET.6,25-27,29 The function of these fusion transcripts appears to be similar to ALK gene fusions in that a coiled-coil domain of the N-terminal of the fusion partner is bound to the kinase domain of RET, which allows RET to dimerize and remain constitutively activated independent of ligand binding.26,30 Rearrangements in RET are reported to be found in approximately 1% to 2% of all adenocarcinomas of the lung, but these mutations may contribute to 6% to 19% of lung adenocarcinomas in never-smokers who are “pan-negative” for other similar oncogenic driver mutations, such as EML4-ALK and ROS1.3,30,31 RET mutations are found with higher frequency in light and never-smokers, younger patients, and in patients of European and Asian descent. The histology of lung cancers harboring RET rearrangements are most commonly moderately to well-differentiated adenocarcinomas; however, there are now rare examples of cancers with adenosquamous histology positive for these mutations as well.31

Preclinical Activity of RET Inhibitors There are currently no drugs available that selectively inhibit only the RET tyrosine kinase. However, several small-molecule multikinase inhibitors that have already been developed for other targets have been found to have preclinical RET RTK inhibitory activity; this is

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KEY POINTS The treatment of non–small cell lung cancer (NSCLC), which was once a disease with exceedingly few treatment options and historically poor outcomes, has begun to transform ➤ The list of identifiable drug targetable genetic mutations in lung cancer is growing fast; one of the newer targets is the RET proto-oncogene ➤ Currently, there are no drugs available that selectively inhibit only the RET tyrosine kinase ➤ Adding RET to the list of mutations examined in all new NSCLC cases would be a logical next step. ➤

true for sorafenib and sunitinib, the well-studied vascular endothelial growth factor (VEGF) inhibitors that are commonly used to treat renal cell carcinoma and hepatocellular carcinoma.32,33 Several drugs already approved for use in RET-mutated medullary thyroid cancer are currently being examined for their efficacy in RET-mutated NSCLC. Vandetanib is a potent multikinase inhibitor that was approved by the FDA for the treatment of patients with medullary thyroid carcinoma in 2011.34 In 2012, vandetanib was tested by Matsubara et al in preclinical trials using a patient-derived, RET-mutated lung adenocarcinoma cell

Several drugs already approved for use in RET-mutated medullary thyroid cancer are currently being examined for their efficacy in RET-mutated NSCLC. line, LC-2/ad, which contained the CCDC6-RET fusion gene. Results from this experiment were the first of its kind to reveal specifically that lung cancer cells with RET mutations were sensitive to inhibition by vandeta­ nib and insensitive to the epidermal growth factor receptor inhibitor gefitinib.35 Suzuki et al were able to corroborate these data in vivo using xenograft models with the same LC-2/ad cell line.36 Finally, Saito et al, using xenograft mice models harboring the most common RET fusion gene in NSCLC, KIF5B-RET, were recently able to prove that vandetanib was effective in significantly reducing tumor burden.37 A second drug with RET inhibitory activity, cabozantinib, was approved for the treatment of medullary thyroid carcinoma in 2012 and is just now beginning to be examined in the setting of NSCLC.38,39

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signaling of both wild-type and mutant forms of RET, with inhibition of RET signaling into the low nanomolar range in cell lines harboring RET-mutated thyroid cancer cells.41,42 At the 2013 Annual Meeting of the American Association for Cancer Research, Gozgit et al presented their data comparing the potency of ponatinib at inhibiting RET in the Ba/F3 cell line engineered to express the most common NSCLC RET fusion gene KIF5B-RET with 4 other TKIs known to inhibit RET. These data are presented in Table 1.43

Table 1 IC50 of RET-Inhibiting TKIs in NSCLC with KIF5B-RET Fusion Genes43 IC50 in Ba/F3 Cells Expressing KIF5B-RET Fusion Genes Cabozantinib

292 nM

Ponatinib

11 nM

Sorafenib

861 nM

Sunitinib

570 nM

Vandetanib

773 nM

IC50 indicates inhibitory concentration of 50%; NSCLC, non–small cell lung cancer; TKI, tyrosine kinase inhibitor.

Lenvatinib is an oral multi-TKI that targets VEGF receptors 1-3, fibroblast growth factor receptors 1-3, RET, mast/stem cell growth factor receptor, and platelet-derived growth factor beta. Cell-free kinase assays suggest that lenvatinib inhibits RET kinase-expressing cell lines. A recent preclinical study by Okamoto et al using LC-2/ad lung cancer cells revealed that in vitro lenvatinib inhibited cell growth with an inhibitory concentration of 50% of 48 nM. Lenvatinib was also found to decrease the percentage of cells in S phase, suggesting that the inhibition of signaling led to arrest of the growth phase.40 Finally ponatinib, a drug currently approved for the treatment of Philadelphia chromosome–positive leukemia, has been shown in vitro by Mologni et al to inhibit

Clinical Activity of RET Inhibitors in Lung Cancer In Vivo The data surrounding use of the previously described RET inhibitors in patients with NSCLC positive for RET mutations are still extremely limited. Although several drugs with multikinase-inhibiting activity including RET are now in phase 2 clinical trials (Table 2), the majority of these trials are still enrolling patients, so formal reports of results are still very sparse. There are only 2 published reports describing the outcome of patients with NSCLC with RET mutations after treatment with one of the previously described RET-inhibiting drugs.

The first, by Drilon et al, is a report of the first 3 patients in their trial testing the drug cabozantinib in patients with RET mutation–positive, advanced NSCLC. The

Table 2 Phase 2 Clinical Trials of RET Inhibitors in NSCLC Sample Size

Trial Number

TKI

Study Design/Official Title

NCT01813734

Ponatinib

20

A Phase II, Open-Label Study of Ponatinib, A Multi-Targeted Oral Tyrosine Kinase Inhibitor, in Advanced Non-Small Cell Lung Cancer Harboring RET Translocations

NCT01639508

Cabozantinib

50

A Phase II Study of Cabozantinib in Patients With RET FusionPositive Advanced Non-Small Cell Lung Cancer and Those With Other Genotypes: ROS1 or NTRK Fusions or Increased MET or AXL Activity

NCT01823068

Vandetanib

17

A Phase II Study of Vandetanib in Patients With Non-small Cell Lung Cancer Harboring RET Rearrangement

NCT01829217

Sunitinib

35

A Phase II Trial of Sunitinib in Never-smokers With Lung Adenocarcinoma: Identification of Oncogenic Alterations Underlying Sunitinib Sensitivity

NCT01877083

Lenvatinib

20

A Multicenter, Open-Label Phase 2 Study of the Safety and Activity of Lenvatinib (E7080) in Subjects With KIF5B-RET-Positive Adenocarcinoma of the Lung

Detailed information about these trials can be found at clinicaltrials.gov.

NSCLC indicates non–small cell lung cancer; TKI, tyrosine kinase inhibitor.

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first patient described was a 41-year-old female with a novel TRIM33-RET fusion. This patient had a durable partial response, with a 66% decrease in disease burden as measured by RECIST and was still on the trial with no reported dose reductions at 20 weeks. The second patient, who was significantly older than the first (75-yearold female) also had a confirmed partial response (33% disease reduction). However, this patient suffered several dose-limiting toxicities, including grade 3 fatigue and grade 3 proteinuria, which required 2 dose reductions.

Despite dose reductions, she remained progression free and continued on the trial at 16 weeks. The third patient was a 68-year-old female who suffered from grade 3 hypertension requiring dose reduction, but she ultimately had disease stabilization with progression-free survival at 8 months.44 In 2013, Gautschi et al published a report of a 58-year-old male with RET-mutated NSCLC refractory to previous chemotherapy who responded to treatment with vandetanib at a dose of 300 mg per day.45

The field of thoracic oncology has enjoyed considerable growth during the past 5 years since the discovery of oncogenic driver mutations.

Discussion The field of thoracic oncology has enjoyed considerable growth during the past 5 years since the discovery of oncogenic driver mutations. For the first time in history, a subset of patients with NSCLC that once had a dismal prognosis are being afforded extended survival and improved quality of life on treatment because of the discovery of new “druggable” driver mutations that allow treatment with targeted therapies such as erlotinib or crizotinib, which have fewer toxicities than standard chemotherapy. The success of these therapies has proved that for patients who harbor one of these driver mutations or fusion proteins, treatment with cytotoxic chemotherapy may not be the safest or most effective option for treatment. Previously published trials examining drugs with RET inhibitory activity (sorafenib, sunitinib, and vandetanib) in patients with NSCLC were not performed in populations selected for RET mutations. So although these drugs were previously thought to have little activity in lung cancer, it is possible they were not being tested in the right subset of patients. Whereas it is true that RET mutations are only found in a small percentage of patients with NSCLC, the benefits that RET-inhibiting drugs may have in the right patient population could be, like crizotinib in ALK-mutated patients, fairly dramatic. The results from the various phase

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2 clinical trials that are limited to patients predetermined to have RET mutations appear promising and will likely be extremely informative as to whether RET will be another useful drug target to help patients with NSCLC survive longer and with a better quality of life on therapy. What is clear is that the similarities between the RET oncogene and the ALK and ROS1 oncogenes are undeniable, and given the potential benefits to a patient population with too few treatment options, it would be a logical next step to add RET to the list of mutations examined in all new NSCLC cases. u

References

1. World Health Organization. Cancer fact sheets. 2015. www.who.int/mediacentre/ factsheets/fs297/en/. Accessed October 28, 2014.

2. Kwak EL, Bong YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693-1703.

3. Suehara Y, Arcila M, Wang L, et al. Identification of KIF5B-RET and GOPC-ROS1 fusions in lung adenocarcinomas through a comprehensive mRNAbased screen for tyrosine kinase fusions. Clin Cancer Res. 2012;18:6599-6608.

4. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311:1998-2006.

5. Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 2011;12:175-180.

6. Lipson D, Capelletti M, Yelensky R, et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med. 2012;18:382-384.

7. Ishizaka Y, Itoh F, Tahira T, et al. Human ret proto-oncogene mapped to chromosome 10q11.2. Oncogene. 1989;4:1519-1521.

8. Airaksinen MS, Titievsky A, Saarma M. GDNF family neurotrophic factor signaling: four masters, one servant? Mol Cellular Neurosci. 1999;13:313-325.

9. Esseghir S, Todd SK, Hunt T, et al. A role for glial cell derived neurotrophic factor induced expression by inflammatory cytokines and RET/GFR alpha 1 receptor up-regulation in breast cancer. Cancer Res. 2007;67:11732-11741.

10. Mulligan LM. RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer.

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11. Tahira T, Ishizaka Y, Itoh F, et al. Characterization of ret proto-oncogene mRNAs encoding two isoforms of the protein product in a human neuroblastoma cell line. Oncogene. 1990;5:97-102.

12. Pachnis V, Mankoo B, Costantini F. Expression of the c-ret proto-oncogene during mouse embryogenesis. Development. 1993;119:1005-1017.

13. Tsuzuki T, Takahashi M, Asai N, et al. Spatial and temporal expression of the ret proto-oncogene product in embryonic, infant and adult rat tissues. Oncogene.

1995;10:191-198.

14. Avantaggiato V, Dathan NA, Grieco M, et al. Developmental expression of the RET protooncogene. Cell Growth Differ. 1994;5:305-311.

15. Takahashi M, Buma Y, Iwamoto T, et al. Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains.

Oncogene. 1988;3:571-578.

16. Anders J, Kjær S, Ibáñez CF. Molecular modeling of the extracellular domain of the RET receptor tyrosine kinase reveals multiple cadherin-like domains and a calcium-binding site. J Biol Chem. 2001;276:35808-35817.

17. Plaza-Menacho I, van der Sluis T, Hollema H, et al. Ras/ERK1/2-mediated STAT3 Ser727 phosphorylation by familial medullary thyroid carcinoma-associated RET mutants induces full activation of STAT3 and is required for c-fos promoter activation, cell mitogenicity, and transformation. J Biol Chem. 2007;282:6415-6424.

18. Arighi E, Borrello MG, Sariola H. RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev. 2005;16:441-467.

19. Mulligan LM, Kwok JB, Healey CS, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993;363:458-460.

20. Donis-Keller H, Dou S, Chi D, et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet. 1993;2:851-856.

21. Romei C, Elisei R. RET/PTC translocations and clinico-pathological features in human papillary thyroid carcinoma. Front Endocrinol (Lausanne). 2012;3:54.

22. Romei C, Fugazzola L, Puxeddu E, et al. Modifications in the papillary thyroid cancer gene profile over the last 15 years. J Clin Endocrinol Metab. 2012;97:E1758E1765.

23. Emison ES, McCallion AS, Kashuk CS, et al. A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk. Nature. 2005;434:857-863.

24. Seri M, Yin L, Barone V, et al. Frequency of RET mutations in long- and short-segment Hirschsprung disease. Hum Mutat. 1997;9:243-249.

25. Ju YS, Lee WC, Shin JY, et al. A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing.

Genome Res. 2012;22:436-445.

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26. Kohno T, Ichikawa H, Totoki Y, et al. KIF5B-RET fusions in lung adenocarcinoma. Nat Med. 2012;18:375-377.

27. Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med. 2012;18:378-381.

28. Li F, Feng Y, Fang R, et al. Identification of RET gene fusion by exon array analyses in “pan-negative” lung cancer from never smokers. Cell Res. 2012;22:928-931.

29. Zheng Z, Liebers M, Zhelyazkova B, et al. Anchored multiplex PCR for targeted next-generation sequencing. Nat Med. 2014;20:1479-1484.

30. Kohno T, Tsuta K, Tsuchihara K, et al. RET fusion gene: translation to personalized lung cancer therapy. Cancer Sci. 2013;104:1396-1400.

31. Wang R, Hu H, Pan Y, et al. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol. 2012;30:4352-4359.

32. Kim DW, Jo YS, Jung HS, et al. An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases. J Clin Endocrinol Metab. 2006;91:4070-4076.

33. Plaza-Menacho I, Mologni L, Sala E, et al. Sorafenib functions to potently suppress RET tyrosine kinase activity by direct enzymatic inhibition and promoting RET lysosomal degradation independent of proteasomal targeting. J Biol Chem.

2007;282:29230-29240.

34. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30:134-141.

35. Matsubara D, Kanai Y, Ishikawa S, et al. Identification of CCDC6-RET fusion in the human lung adenocarcinoma cell line, LC-2/ad. J Thorac Oncol. 2012;7:18721876.

36. Suzuki M, Makinoshima H, Matsumoto S, et al. Identification of a lung adeno-

carcinoma cell line with CCDC6-RET fusion gene and the effect of RET inhibitors in vitro and in vivo. Cancer Sci. 2013;104:896-903.

37. Saito M, Ishigame T, Tsuta K, et al. A mouse model of KIF5B-RET fusion-dependent lung tumorigenesis. Carcinogenesis. 2014;35:2452-2456.

38. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-3646.

39. Kurzrock R, Sherman SI, Ball DW, et al. Activity of XL184 (cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol.

2011;29:2660-2666.

40. Okamoto K, Kodama K, Takase K, et al. Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models. Cancer Lett. 2013;340:97-103.

41. Mologni L, Redaelli S, Morandi A, et al. Ponatinib is a potent inhibitor of wildtype and drug-resistant gatekeeper mutant RET kinase. Mol Cell Endocrinol.

2013;377:1-6.

42. De Falco V, Buonocore P, Muthu M, et al. Ponatinib (AP24534) is a novel potent inhibitor of oncogenic RET mutants associated with thyroid cancer. J Clin Endocrinol Metab. 2013;98:E811-E819.

43. Gozgit JM, Chen T, Clackson T, et al. Ponatinib is a highly potent inhibitor of activated variants of RET found in MTC and NSCLC. Paper presented at: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; April 6-10, 2013; Washington, DC. Abstract 2084.

44. Drilon A, Wang L, Hasanovic A, et al. Response to cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov. 2013;3:630-635.

45. Gautschi O, Zander T, Keller FA, et al. A patient with lung adenocarcinoma and RET fusion treated with vandetanib. J Thorac Oncol. 2013;8:e43-e44.

WORLD CUTANEOUS MALIGNANCIES CONGRESS ™

A Special Session at the Fourth Annual PMO Live Conference

July 24-25, 2015 The Westin Seattle Seattle, Washington

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LOOK TO ZELBORAF EXPERIENCE The first treatment approved for BRAF V600E(+) unresectable or metastatic melanoma More than 7000 patients with metastatic melanoma treated since 20111*

*Estimated number of metastatic melanoma patients treated with ZELBORAF from August 2011 to July 2014.

Learn more at Zelboraf.com/EXPERIENCE Indication and Usage ZELBORAF® (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.

ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma.

Important Safety Information The following can occur in patients treated with ZELBORAF: New primary malignancies including cutaneous squamous cell carcinoma, non-cutaneous squamous cell carcinoma, new primary melanoma, and other malignancies Tumor promotion in BRAF wild-type melanomas Serious hypersensitivity reactions including anaphylaxis Severe dermatologic reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis QT prolongation

© 2014 Genentech USA, Inc. All rights reserved. ZBF/120514/0064 Printed in USA.

Hepatotoxicity including liver injury leading to functional hepatic impairment (including coagulopathy or other organ dysfunction); increases in transaminases and bilirubin when concurrently administered with ipilimumab Photosensitivity Ophthalmologic reactions ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action.

The most common adverse reactions of any grade (≥30%) reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/ medwatch. You may also report side effects to Genentech at (888) 835-2555.

Please see accompanying Brief Summary of Prescribing Information for additional Important Safety Information.

Reference: 1. Data on file, Genentech, Inc.

ZELBORAF ® (vemurafenib) tablet for oral use Initial U.S. Approval: 2011 This is a brief summary of information about ZELBORAF. Before prescribing, please refer to the full Prescribing Information.

1 INDICATIONS AND USAGE ZELBORAF ® is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.

Limitation of Use: ZELBORAF is not indicated for treatment of patients with wild-type BRAF melanoma [see Warnings and Precautions (5.2)].

5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF compared to those in the control arm in Trial 1. The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was 24% compared to < 1% in the dacarbazine arm [see Adverse Reactions (6.1)]. The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving ZELBORAF experienced at least one additional occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC observed in clinical studies using ZELBORAF included age (≥ 65 years), prior skin cancer, and chronic sun exposure.

In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to none of the patients receiving dacarbazine.

Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF. Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF [see Adverse Reactions (6.1)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC. Other Malignancies Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies.

5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see Indications and Usage (1)].

5.3 Hypersensitivity Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction [see Adverse Reactions (6.2)].

5.4 Dermatologic Reactions Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction [see Adverse Reactions (6.1)].

5.5 QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.6)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes.

Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of ZELBORAF for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated.

Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias).

5.6 Hepatotoxicity Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with ZELBORAF [see Adverse Reactions (6.1)]. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated.

Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation.

Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see Indications and Usage (1)]. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see Drug Interactions (7.3)].

5.7 Photosensitivity Mild to severe photosensitivity can occur in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors.

Institute dose modifications for intolerable Grade 2 or greater photosensitivity.

5.8 Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis.

5.9 Embryo-Fetal Toxicity ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action.

There are no adequate and well-controlled studies in pregnant women.

If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.

This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14)]. Trial 1 randomized (1:1) 675 treatment-naive patients with unresectable or metastatic melanoma to receive ZELBORAF 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily.

Table 1 presents adverse reactions reported in at least 10% of patients treated with ZELBORAF. The most common adverse reactions of any grade (≥ 30% in either study) in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma.

The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash.

The incidence of Grade 4 adverse reactions was ≤ 4% in both studies.

The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2.

Table 1 Adverse Reactions Reported in ≥ 10% of Patients Treated with ZELBORAF* Trial 2: Patients with Failure of at Least One Prior Systemic Therapy Dacarbazine ZELBORAF n= 287 n= 132 Grade Grade All All Grades 3a Grades 3 (%) (%) (%) (%)

Trial 1: Treatment Naïve Patients

ADRs

Skin and subcutaneous tissue disorders Rash Photosensitivity reaction Alopecia Pruritus Hyperkeratosis Rash maculo-papular Actinic keratosis Dry skin Rash papular Erythema Musculoskeletal and connective tissue disorders Arthralgia Myalgia Pain in extremity Musculoskeletal pain Back pain General disorders and administration site conditions Fatigue Edema peripheral Pyrexia Asthenia Gastrointestinal disorders Nausea Diarrhea Vomiting Constipation Nervous system disorders Headache Dysgeusia Neoplasms benign, malignant and unspecified (includes cysts and polyps) Skin papilloma Cutaneous SCC†# Seborrheic keratosis Investigations Gammaglutamyltransferase increased Metabolism and nutrition disorders Decreased appetite Respiratory, thoracic and mediastinal disorders Cough Injury, poisoning and procedural complications Sunburn

ZELBORAF n= 336 Grade All Grades 3a (%) (%) 37 33 45 23 24 9 8 19 5 14

8 3 <1 1 1 2 0 0 <1 0

2 4 2 1 <1 <1 3 1 0 2

0 0 0 0 0 0 0 0 0 0

52 49 36 30 28 21 17 16 13 8

7 3 0 2 0 6 0 0 0 0

53 13 18 8 8

4 <1 <1 0 <1

3 1 6 4 5

<1 0 2 <1 <1

67 24 9 11 11

8 <1 0 0 <1

38 17 19 11

2 <1 <1 <1

33 5 9 9

2 0 <1 <1

54 23 17 2

4 0 2 0

35 28 18 12

2 <1 1 <1

43 13 26 24

2 <1 1 0

37 29 26 16

2 <1 2 0

23 14

<1 0

10 3

0 0

27 11

0 0

21 24 10

<1 22 <1

0 <1 1

0 <1 0

30 24 14

0 24 0

5

3

1

0

15

6

18

0

8

<1

21

0

8

0

7

0

12

0

10

0

0

0

14

0

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. a Grade 4 adverse reactions limited to gamma-glutamyltransferase increased (< 1% in Trial 1 and 4% in Trial 2). † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol.

Clinically relevant adverse reactions reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, panniculitis, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: neuropathy peripheral, VII th nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinoma Infections and infestations: folliculitis Eye disorders: retinal vein occlusion Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4.

Table 2 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

0 * For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ZELBORAF. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Progression of a pre-existing chronic myelomonocytic leukemia with NRAS mutation [see Warnings and Precautions (5.1)].

Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) [see Warnings and Precautions (5.3)].

Blood and lymphatic systems disorder: Neutropenia 7 DRUG INTERACTIONS 7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations [see Clinical Pharmacology (12.3)].

Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible.

7.2 Effect of Vemurafenib on CYP1A2 Substrates Concomitant use of ZELBORAF with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as ZELBORAF may increase concentrations of CYP1A2 substrates.

If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates.

7.3 Ipilimumab Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF [see Warnings and Precautions Section 5.6].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)].

ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action.

Vemurafenib revealed no evidence of teratogenicity in rat embryo/fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3–5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

8.3 Nursing Mothers It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use Safety and efficacy in pediatric patients below the age of 18 have not been established.

8.5 Geriatric Use Clinical studies of ZELBORAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Hepatic Impairment No formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis. The appropriate dose of ZELBORAF has not been established in patients with severe hepatic impairment.

8.7 Renal Impairment No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis. The appropriate dose of ZELBORAF has not been established in patients with severe renal impairment.

10 OVERDOSAGE There is no information on overdosage of ZELBORAF. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide).

Health care providers should advise patients of the potential benefits and risks of ZELBORAF and instruct their patients to read the Medication Guide before starting ZELBORAF therapy. Inform patients of the following: • Evidence of BRAF V600E mutation in the tumor specimen with an FDA approved test is necessary to identify patients for whom treatment with ZELBORAF is indicated [see Dosage and Administration (2.1)].

• ZELBORAF increases the risk of developing new primary cutaneous malignancies. Advise patients of the importance of contacting their health care provider immediately for any changes in their skin [see Warnings and Precautions (5.1)].

• Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Advise patients to stop taking ZELBORAF and to seek immediate medical attention for symptoms of anaphylaxis or hypersensitivity [see Warnings and Precautions (5.3)].

• Severe dermatologic reactions can occur in patients receiving ZELBORAF. Advise patients to stop taking ZELBORAF and to contact their health care provider for severe dermatologic reactions [see Warnings and Precautions (5.4)].

• ZELBORAF can prolong QT interval, which may result in ventricular arrhythmias. Advise patients of the importance of monitoring of their electrolytes and the electrical activity of their heart (via an ECG) during ZELBORAF treatment [see Warnings and Precautions (5.5)].

• Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with ZELBORAF. Advise patients of the importance of laboratory monitoring of their liver during ZELBORAF treatment and to contact their health care provider for relevant symptoms [see Warnings and Precautions (5.6)].

• ZELBORAF can cause mild to severe photosensitivity. Advise patients to avoid sun exposure, wear protective clothing, and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn [see Warnings and Precautions (5.7)].

• Ophthalmologic reactions can occur in patients treated with ZELBORAF. Advise patients to contact their health care provider immediately for ophthalmologic symptoms [see Warnings and Precautions (5.8)].

• ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Advise women of childbearing potential and men to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. Advise patients to contact their health care provider immediately if they become pregnant [see Warnings and Precautions (5.9) and Use in Special Populations (8.1)].

Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990

ZBF/111914/0015 Initial U.S. Approval: August 2011 © 2014 Genentech, Inc

PMO LIVE

Case: Former Smoker with WellDifferentiated Adenocarcinoma of the Lung Genetic tumor profiling, immune profiling, and immunohistocompatibility expression profiling are performed routinely at Yale Cancer Center for patients diagnosed with cancer. The results are presented to the multidisciplinary Molecular Tumor Board, which meets weekly to make treatment decisions. The following case exemplifies a personalized medicine approach and was presented by Roy S. Herbst, MD, PhD, at the Third Annual PMO Live conference.

Safety:10"

Case: Non–Small Cell Lung Cancer A 77-year-old former smoker (25-pack-year history) presented for a second opinion regarding newly diagnosed non– small cell lung cancer. The patient had noticed increased dyspnea on exertion over past year, and cough with sputum production.

A chest radiograph showed a left upper lobe (LUL) mass.

Computed tomography showed a 25×14-mm irregular LUL paramediastinal parenchymal lesion abutting the pleura. Pulmonary function tests revealed normal lung function. Brain magnetic resonance images were negative. LUL core biopsy revealed well-differentiated adenocarcinoma of the lung.

The patient underwent robotic lobectomy with lymph node dissection. Pathology revealed a 4-cm moderately to well-differentiated adenocarcinoma of the lung with 50% papillary, 30% acinar, and 20% micropapillary histology. Bronchial and vascular margins were negative.

The patient had evidence of visceral pleural invasion.

One lymph node, L12, was positive for carcinoma; the others were negative.

Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven, CT. Single nucleotide variants with >10% frequency were present at ERCC4, CDKN4A, EGFR, and FGFR4 (Table). “The one that stands out is an EGFR in-frame deletion in exon 19, which is quite common,” he said. Thirty-three percent of the tumor DNA had this mutation.

Roy S. Herbst, MD, PhD

How Would You Treat the Patient?

Mutations in exons 19 and 21 are known to have response rates to an EGFR tyrosine kinase inhibitor (TKI) of as high as 80%. These mutations are most common in never-smokers, females, patients with East Asian ethnicity, and adenocarcinomas.

The patient felt well overall after surgery. Adjuvant chemotherapy was recommended before the results from sequencing were known. The Molecular Tumor Board recommended chemotherapy and suggested consideration of an EGFR TKI on progression. Approved and Would You Recommend Tumor Genetic Profiling? investigational agents for this mutation are first-generaTumor tissue was tested in a 409-gene panel. “You tion reversible TKIs (gefitinib, erlotinib), the second-genwould at least need to know ALK fusion and EGFR mueration irreversible TKI afatinib, and third-generation Case'#1,'Adenocarcinoma'of'the'Lung' tation status,” said Herbst, Chief of Medical Oncology, mutation-specific TKIs (CO-1686, AZD9291). u

Results'of'409-Cancer'Gene'Panel'

Table

Results from 409-Gene Panel

Tumor&DNA&from&le-&upper&lobectomy&(manually&microdissected,&~60%&malignant& cells);&nontumor&DNA&from&histologically&normal&lymph&node&(nl&ref)&

Single'nucleo@de'variants'(SNVs;!>10%&frequency)& ' Gene'''

' Coding' Ploidy' Altera@on'

Amino'Acid' Muta@on' Change' && Type'

Tumor' Predicted' Normal' DNA'Freq' Effect' DNA'Freq'

ERCC4

3

c.31G>A

p.Ala11Thr

Missense

49%

Minor

0%

CDKN4A

1

c.238C>T

p.Arg80*

Nonsense

39%

Major

0%

EGFR&

2

In frame deletion --

Major

0%

2

p.Glu746_ Ala750del --

33%

FGFR4

c.2235_2249delGGAAT TAAGAGAAGC c.5’UTR C>A

26%

None

0%

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Case Studies: Incorporating Molecular Biomarkers into Therapy for Breast Cancer Is Fraught with Difficulty

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any therapeutic agents target HER2-positive breast cancer. Unfortunately, patient selection for these agents has not been refined, so all HER2-positive patients receive them. In estrogen receptor (ER)-positive disease, new agents improve the response to hormone-targeted therapies, but again, the appropriate patients for targetHope S. Rugo, MD ed agents have not been defined. “Because many agents work for the treatment of breast cancer, it’s a little more difficult to identify the specific subsets for which these targeted agents will be most important,” said Hope S. Rugo, MD, speaking at the Third Annual PMO Live conference.

There are no data to suggest improvement in outcome by doing genomic profiling before selecting a treatment in patients with breast cancer.

At this time, selecting agents based on genomic profiling in breast cancer is experimental. There are no data to suggest improvement in outcome by doing profiling before selecting a treatment in patients with breast cancer, said Rugo, Director, Breast Oncology and Clinical Trials Education, University of California, San Francisco (UCFS). “Most of the time, agents are off-label, so it has to be done in the setting of a clinical trial,” she said.

The promise of genomics in the clinic is to enhance prognosis and prediction and to discover new “actionable” targets. Genomic assays for use in breast cancer are the Recurrence Score and MammaPrint.

“One of the big issues that we face in breast cancer is heterogeneity,” she said. Recent data in breast cancer suggest that metastatic sites may have different markers than the primary tumor sites, “so there’s a big question about what we want to be following when we’re treating patients,” she said. “Almost all data to date that have used genetic markers to try to identify a subset of patients that respond to a specific targeted agent have used primarily archived tumor tissue from the primary tumor site.

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That’s one particular problem that we have.” Heterogeneity within the tumor itself poses the same problems.

Heterogeneity of assays also exists, and standardization of assays, interpretation, and reporting are needed, said Rugo.

Recent studies have identified 4 to 7 different subtypes of triple-negative breast cancer. “The key here is identifying the targets,” she said. The targets may span these subtypes, but clearly these are all great laboratories doing excellent work, and they’re coming up with different information because of different platforms.

One of the questions is whether genomic assays aid in determination of treatment or confuse the picture. I think in breast cancer, specifically, that these tests need to be done in the setting of a clinical trial and not as a clinical service.”

Case: Invasive Ductal Cancer A 43-year-old woman presented with a 1.2-cm, grade 3, invasive ductal cancer that was ER-positive in 60% of cells, progesterone receptor (PR)-positive in 5% to 10% of cells, with a HER2/chromosome 17 ratio of 1.1 (clearly not amplified).

Her oncologist sent a Recurrence Score, which was 31.

The high Recurrence Score suggested the addition of chemotherapy to the patient’s hormone therapy. Her ER score was negative at 6.4, her PR score was negative at 5.2, and HER2 was equivocal at 10.8.

Before the patient was referred to us, a MammaPrint assay was ordered and came back showing high-risk, ER-negative, PR–very low positive, HER2-negative, luminal type disease.

Repeat immunohistochemistry (IHC) and fluoresence in situ hybridization (FISH) studies at UCSF showed ER/PR positivity by IHC but a clearly negative bioexpression analysis. The HER2 test was indeterminate. On FISH, the mean ErbB2 signals per nucleus was 6.0, which is positive by the new American Society of Clinical Oncology/College of American Pathologists guidelines. The ratio was clearly negative at 1.1.

The Recurrence Score was repeated and came back identical to the first (31), meaning high risk of recurrence with tamoxifen alone. The ER score was borderline negative, the PR score was negative, and the HER2 score was equivocal.

This case highlights some of the difficulties with the use of large expression panels to determine treatment.

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“Essentially, we didn’t know what the right answer was for this tumor,” said Rugo. The woman was treated with chemotherapy, trastuzumab, and hormone therapy and is doing very well a number of years later.

Case: Value of Sampling A 78-year-old woman presented with a 2.3-cm, node-negative, pleomorphic and classic lobular cancer. It was ER/PR–strongly positive, grade 2. The Recurrence Score was 33, and this time, the assay came back as ER/ PR negative. Pathology review found 2 clearly different areas within the tumor: one strongly positive for ER with classic lobular histology, and the other pleomorphic and ER negative.

This woman was treated with adjuvant chemother­ apy (cyclophosphamide, methotrexate, and fluorouracil for 8 cycles) and has done very well. She continues to take hormone therapy and is about 4 years out from diagnosis.

Mutation-Matched Therapy Finding a genetic mutation does not necessarily lead to improved outcome with a matched therapy. In a clinical trial randomizing patients to receive hormone therapy with or without an mTOR inhibitor (J Clin Oncol. 2013;31[suppl]. Abstract LBA509), there was no difference in progression-free survival (PFS) based on whether the patient had wild-type or a single mutation in either PI3-kinase or the fibroblast growth factor receptor or PTEN, which are the most frequently altered genes. Fifty percent of patients in the trial had alterations in PI3-kinase, but it didn’t predict PFS, said Rugo.

Prognosis is very poor with multiple mutations. “We don’t know what to do when patients have multiple mutations, because we don’t know which one is the most important in driving the poor outcome,” she said.

In the phase 3 CLEOPATRA biomarker analysis (Cancer Res. 2012;72[24 Suppl]. Abstract S5-1), PIK3CA mutation was associated with a poorer prognosis in both the placebo and pertuzumab arms. Mutations in PIK3CA were not associated with resistance to pertuzumab because patients derived similar additional benefits independent of PIK3CA mutational status. The same was true of other mutations that were evaluated in the trial. “Unfortunately, all the mutation analysis did was give us prognostic information,” said Rugo.

Case: Activating HER2 Mutations A 58-year-old woman presented with a node-negative, ER-positive, HER2-positive invasive ductal cancer. She received endocrine therapy and radiation per current National Comprehensive Cancer Network guidelines. She then

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presented with inflammatory disease with extensive involvement of skin, breast, and regional nodes.

On biopsy, the tumor was ER/PR/HER2-negative, and this was repeated. She received multiple lines of therapy over a course of about 2 years with little evidence of response, but with progression of disease, extensive skin involvement, reduced range of motion, and fungal pneumonia.

Her tumor was sent for next-generation sequencing.

Two activating ErbB2 mutations were found that in preclinical data have been shown to be sensitive to both trastuzu­ mab and lapatinib in lung cancer. In addition, the patient might qualify for entry into clinical trials of heat shock protein 90–targeted agents.

The woman received HER2-targeted therapy in a clinical trial, using the HER2 tyrosine kinase inhibitor neratinib in combination with chemotherapy.

Positron emission tomography showed symptomatic and objective improvement. The improvement was quite durable, with a response duration of 8 months, and it was the only treatment to which her cancer responded.

Unfortunately, finding actionable targets is not true for most breast tumors, as the next case demonstrates.

We don’t know what to do when patients have multiple mutations, because we don’t know which one is the most important in driving the poor outcome.

Case: Driver Mutations in Breast Cancer: Few Have Matched Therapy A 45-year-old physician presented with a node-positive, high-grade, triple-negative breast cancer treated with adjuvant chemotherapy. She had a recurrence at 12 months with a large mediastinal mass and compression/shift of major vessels and airways.

Pathology showed her to have a triple-negative breast cancer, high grade, with spindle cells. A tumor sample was sent to Caris Target Now, and a list of potentially active chemotherapy agents was generated. They included the drugs that she had already received in the adjuvant setting.

Through genomic sequencing, 6 genomic alterations were discovered (AKT2 amplification, PTEN, PIK3CA, CDKN2A/B loss, MYC amplification, and TP53), most of which have no matched drug at present.

“The role of next-generation sequencing remains unclear in breast cancer; it’s primarily a research tool,” said Rugo. “I don’t think we should be spending a lot of money in our breast cancer patients on it outside the setting of a clinical trial. We need the ability to look at

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panels of genes correlated to clinical phenotype and outcome.”

The most common driver mutations in breast cancer still only occur in less than 10% of patients. “We’re going to have to have trials where we’re identifying treatments for tiny numbers of patients,” she said. Be-

The AURORA trial is an international trial with a planned component of basket trials in which cancer patients are entered based on their mutational status. cause of the low frequency of each of the driver mutations in metastatic breast cancer, thousands of patients may need to be screened to find a single patient with a genomic alteration that is actionable.

“We’re going to have to do that as a group,” she said.

One trial, SAFIR 01, accrued 423 patients and had 404

biopsy samples. Comparative genomic hybridization (CGH) arrays in 287 found targetable alterations in 194 (67%). “However, most of these were rare, and there were no drugs to target them,” she said. “They gave treatment driven by genomics to only 48 patients (25%) and 4 with CGH-identified ErbB2 amplification.” The objective response rate was 9%, and the rate of overall response plus stable disease at 16 weeks was 28%.

Adaptive trial designs in which patients are randomized based on their interim responses to treatments is one approach to overcome this hurdle. “We may be able to identify specific subtypes of breast cancer within our broader groups that respond to targeted agents,” said Rugo. “Those agents will go into phase 3 trials in the neoadjuvant setting.”

The AURORA trial is an international trial with a planned component of basket trials in which cancer patients are entered based on their mutational status.

As part of the trial, patients have access to specific drugs not approved for disease, based on genomic profiling. u

REGISTER TODAY JULY 22-25, 2015 THE WESTIN SEATTLE • SEATTLE, WASHINGTON

CONFERENCE CO-CHAIRS

Sanjiv S. Agarwala, MD

Jorge E. Cortes, MD

Professor of Medicine Temple University School of Medicine Chief, Medical Oncology & Hematology St. Luke’s Cancer Center Bethlehem, PA

Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

Hope S. Rugo, MD

Professor of Medicine Director, Breast Oncology and Clinical Trials Education UCSF Helen Diller Family Hope Comprehensive S. Rugo, M.D. Cancer Center San of Francisco, Professor MedicineCA Director, Breast Oncology andPMOLive_fi Clinical Trials Education ll042415 University of California San Francisco Helen Diller Family Cancer Center San Francisco, CA

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Hope S. Rugo, MD, is a Professor of Medicine in the Divisi the University of California San Francisco, Helen Diller Fa where she directs Breast Cancer and Clinical Trial Educatio June Vol cancer, 4, Noimmune 3 novel therapies for2015 advanced breast modul sensitivity, evaluation of circulating cells as novel markers

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VALCHLOR® (mechlorethamine) gel is an alkylating drug indicated for the topical treatment of Stage IA and IB mycosis fungoides–type cutaneous T-cell lymphoma (MF-CTCL) in patients who have received prior skin-directed therapy WHEN IT’S TIME TO MANAGE THE CHALLENGES OF STAGE IA AND IB MF-CTCL

VALCHLOR IS ON IT The first and only FDA-approved topical formulation of mechlorethamine (commonly known as nitrogen mustard) • Proven efficacy in a 12-month study 1 • Once-daily gel (special handling and disposal procedures should be followed)

• Dependable formulation manufactured with consistent quality and potency • Comprehensive resources provided by VALCHLOR Support ™

For more information, including how to prescribe, visit www.valchlor.com or call 1-855-4-VALCHLOR (1-855-482-5245).

DOSING AND APPLICATION VALCHLOR is for topical dermatologic use only. Apply a thin film of gel once daily to affected areas of the skin. VALCHLOR is a cytotoxic drug and special handling and disposal procedures should be followed during use. Caregivers must wear disposable nitrile gloves when applying VALCHLOR. Patients and caregivers must wash hands thoroughly after handling or applying VALCHLOR.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS VALCHLOR is contraindicated in patients with known severe hypersensitivity to mechlorethamine. Hypersensitivity reactions, including anaphylaxis, have occurred with topical formulations of mechlorethamine.

WARNINGS AND PRECAUTIONS • Mucosal or eye injury: Exposure of mucous membranes to mechlorethamine such as the oral mucosa or nasal mucosa causes pain, redness, and ulceration, which may be severe.

Exposure of the eyes causes pain, burns, inflammation, photophobia, and blurred vision. Blindness and severe irreversible anterior eye injury may occur. Should eye exposure or mucosal contact occur, immediately irrigate for at least 15 minutes with copious amounts of water, followed by immediate medical consultation • Secondary exposure: Avoid direct skin contact with VALCHLOR in individuals other than the patients due to risk of dermatitis, mucosal injury, and secondary cancers

• Dermatitis: Dermatitis may be moderately severe or severe.

Monitor patients for redness, swelling, inflammation, itchiness, blisters, ulceration, and secondary skin infections.

Stop treatment with VALCHLOR or reduce dose frequency • Non-melanoma skin cancer: Monitor patients during and after treatment with VALCHLOR • Embryo-fetal toxicity: Women should avoid becoming pregnant while using VALCHLOR due to the potential hazard to the fetus. For nursing mothers, discontinue use of VALCHLOR or nursing • Flammable gel: VALCHLOR is an alcohol-based gel. Avoid fire, flame, and smoking until the gel has dried

ADVERSE REACTIONS The most common adverse reactions (≥5%) were dermatitis (56%), pruritus (20%), bacterial skin infection (11%), skin ulceration or blistering (6%), and skin hyperpigmentation (5%). These reactions may be moderately severe or severe.

Elderly patients aged 65 and older may be more susceptible. Depending on severity, treatment reduction, suspension, or discontinuation may be required.

To report SUSPECTED ADVERSE REACTIONS, contact Actelion Pharmaceuticals US, Inc., at 1-855-4-VALCHLOR (1-855-482-5245) or FDA at 1-800-FDA-1088 or visit www.fda.gov/medwatch.

Please see Brief Summary of Prescribing Information on adjacent page.

REFERENCE: 1. VALCHLOR [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc.; 2013.

VALCHLOR®and VALCHLOR Support™ are trademarks of Actelion Pharmaceuticals Ltd. © 2014 Actelion Pharmaceuticals US, Inc. All rights reserved. VAL-00163 0814

A great idea finally gels

VALCHLOR® (mechlorethamine) gel, 0.016% For Topical Dermatological Use Only BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION This brief summary does not include all the information needed to use VALCHLOR safely and effectively. See Full Prescribing Information for VALCHLOR. • INDICATIONS AND USAGE VALCHLOR is an alkylating drug indicated for the topical treatment of Stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma in patients who have received prior skin-directed therapy.

• CONTRAINDICATIONS The use of VALCHLOR is contraindicated in patients with known severe hypersensitivity to mechlorethamine. Hypersensitivity reactions, including anaphylaxis, have occurred with topical formulations of mechlorethamine.

• WARNINGS AND PRECAUTIONS >> Mucosal or Eye Injury Exposure of the eyes to mechlorethamine causes pain, burns, inflammation, photophobia, and blurred vision. Blindness and severe irreversible anterior eye injury may occur. Advise patients that if eye exposure occurs, (1) immediately irrigate for at least 15 minutes with copious amounts of water, normal saline, or a balanced salt ophthalmic irrigating solution and (2) obtain immediate medical care (including ophthalmologic consultation).

Exposure of mucous membranes such as the oral mucosa or nasal mucosa causes pain, redness, and ulceration, which may be severe. Should mucosal contact occur, immediately irrigate for at least 15 minutes with copious amounts of water, followed by immediate medical consultation. >> Secondary Exposure to VALCHLOR Avoid direct skin contact with VALCHLOR in individuals other than the patient. Risks of secondary exposure include dermatitis, mucosal injury, and secondary cancers. Follow recommended application instructions to prevent secondary exposure. >> Dermatitis The most common adverse reaction was dermatitis, which occurred in 56% of the patients. Dermatitis was moderately severe or severe in 23% of patients.

Monitor patients for redness, swelling, inflammation, itchiness, blisters, ulceration, and secondary skin infections. The face, genitalia, anus, and intertriginous skin are at increased risk of dermatitis. Follow dose modification instructions for dermatitis. >> Non-Melanoma Skin Cancer Four percent (4%, 11/255) of patients developed a non-melanoma skin cancer during the clinical trial or during one year of post-treatment follow-up: 2% (3/128) of patients receiving VALCHLOR and 6% (8/127) of patients receiving the mechlorethamine ointment comparator. Some of these non-melanoma skin cancers occurred in patients who had received prior therapies known to cause non-melanoma skin cancer. Monitor patients for non-melanoma skin cancers during and after treatment with VALCHLOR. Non-melanoma skin cancer may occur on any area of the skin, including untreated areas. >> Embryo-fetal Toxicity Based on its mechanism of action, case reports in humans, and findings in animals, VALCHLOR can cause fetal harm when administered to a pregnant woman. There are case reports of children born with malformations in pregnant women systemically administered mechlorethamine. Mechlorethamine was teratogenic and embryo-lethal after a single subcutaneous administration to animals. Advise women to avoid becoming pregnant while using VALCHLOR. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. >> Flammable Gel Alcohol-based products, including VALCHLOR, are flammable. Follow recommended application instructions.

• ADVERSE REACTIONS In a randomized, observer-blinded, controlled trial, VALCHLOR 0.016% (equivalent to 0.02% mechlorethamine HCl) was compared to an Aquaphor ®-based mechlorethamine HCl 0.02% ointment (Comparator). The maximum duration of treatment was 12 months. Sixty-three percent (63%) of patients in the VALCHLOR arm and 67% in the comparator arm completed 12 months of treatment.

The body system associated with the most frequent adverse reactions was skin and subcutaneous tissue disorders. The most common adverse reactions (occurring in at least 5% of the patients) are shown in Table 1.

Table 1. Most Commonly Reported (≥5%) Cutaneous Adverse Reactions Comparator VALCHLOR N=127 N=128 % of patients % of patients Any ModeratelyAny ModeratelyGrade Severe or Severe Grade Severe or Severe Dermatitis 56 23 58 17 Pruritus 20 4 16 2 Bacterial skin infection 11 2 9 2 Skin ulceration or blistering 6 3 5 2 Skin hyperpigmentation 5 0 7 0 In the clinical trial, moderately-severe to severe skin-related adverse events were managed with treatment reduction, suspension, or discontinuation.

Discontinuations due to adverse reactions occurred in 22% of patients treated with VALCHLOR and 18% of patients treated with the comparator. Sixty-seven percent (67%) of the discontinuations for adverse reactions occurred within the first 90 days of treatment. Temporary treatment suspension occurred in 34% of patients treated with VALCHLOR and 20% of patients treated with the comparator.

Reductions in dosing frequency occurred in 23% of patients treated with VALCHLOR and 12% of patients treated with the comparator.

Reductions in hemoglobin, neutrophil count, or platelet count occurred in 13% of patients treated with VALCHLOR and 17% treated with Comparator.

• DRUG INTERACTIONS No drug interaction studies have been performed with VALCHLOR. Systemic exposure has not been observed with topical administration of VALCHLOR; therefore, systemic drug interactions are not likely.

• USE IN SPECIFIC POPULATIONS >> Pregnancy Pregnancy Category D Risk Summary Mechlorethamine can cause fetal harm when administered to a pregnant woman. There are case reports of children born with malformations to pregnant women systemically administered mechlorethamine. Mechlorethamine was teratogenic in animals after a single subcutaneous administration. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Animal Data Mechlorethamine caused fetal malformations in the rat and ferret when given as single subcutaneous injections of 1 mg/kg. Other findings in animals included embryolethality and growth retardation when administered as a single subcutaneous injection. >> Nursing Mothers It is not known if mechlorethamine is excreted in human milk. Due to the potential for topical or systemic exposure to VALCHLOR through exposure to the mother’s skin, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother. >> Pediatric Use Safety and effectiveness in pediatric patients have not been established. >> Geriatric Use A total of 79 patients age 65 and older (31% of the clinical trial population) were treated with either VALCHLOR or the comparator in the clinical trial. Forty-four percent (44%) of patients age 65 or older treated with VALCHLOR achieved a Composite Assessment of Index Lesion Severity (CAILS) response compared to 66% of patients below the age of 65. Seventy percent (70%) of patients age 65 and older experienced cutaneous adverse reactions and 38% discontinued treatment due to adverse reactions, compared to 58% and 14% in patients below the age of 65, respectively. Similar differences in discontinuation rates between age subgroups were observed in the comparator group.

Manufactured for: Actelion Pharmaceuticals US, Inc. South San Francisco, CA 94080, USA © 2014 Actelion Pharmaceuticals US, Inc. All rights reserved.

VAL-00170 0814

EUROPEAN LUNG CANCER CONFERENCE

DNA Blood Testing May Be an Alternative to Tumor Sampling for Identifying EGFR Mutations

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irculating cancer DNA in the blood of cancer patients appears to be able to provide information similar to that obtained from tumor tissue sampling, according to a study presented at the European Lung Cancer Conference. This makes blood testing for DNA an attractive option in cases where tumor tissue is not available.

These results have important implications for selection of targeted therapies aimed at specific cancer mutations, said presenting author Martin Reck, MD, Department of Thoracic Oncology at Lung Clinic Grosshansdorf, Germany.

There are circumstances where it is difficult, if not impossible, to obtain tumor tissue for genetic testing, he explained, and studies suggest that DNA from the tumor that circulates in the bloodstream can identify mutations present in the tumor. To test this assumption, the large international ASSESS trial compared the ability of blood testing versus standard tumor tissue testing to detect EGFR mutations.

There are circumstances where it is difficult, if not impossible, to obtain tumor tissue for genetic testing.

“We were really asking a question on behalf of patients. Is there a valid test that can identify an EGFR mutation and give me the opportunity for superior treatment, even if my lung tumor is not accessible for bronchoscopy or CT-guided biopsy? And, are the results of this blood test in agreement with the results of the ‘gold-standard’ tissue test?” Reck stated in a press release from the European Society of Medical Oncology.

The investigators assessed 1162 matched tumor tissue and blood samples for the presence of an EGFR

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mutation in lung cancer patients. An 89% agreement was found between the 2 types of tests. Plasma testing identified about half of the patients with EGFR mutations compared with tumor tissue sampling, for a sensitivity of 46%.

Refinements have improved the sensitivity of these tests, so in the future it should be possible to do a better job at finding EGFR and other genetic mutations.

Reck pointed out that the tests in this study were performed in local labs used in routine clinical practice, not in a centralized lab selected for a clinical trial. This makes the results more reflective of the “clinical reality, and not a ‘virtual’ trial reality,” he said.

The present study showed that the presence of EGFR mutations in circulating DNA from plasma or serum can be detected in about half of patients with the testing techniques used in this study. Commenting on the study, Rafael Rosell, MD, Catalan Institute of Oncology, Barcelona, Spain, noted that since the trial was conducted, refinements in blood tests for circulating DNA have improved the sensitivity of these tests, so in the future it should be possible to do a better job at finding EGFR and other genetic mutations.

“Cell-free DNA detected in the bloodstream of cancer patients represents an excellent tool to examine genetic alterations that are usually found through tumor tissue testing. This represents one of the most astonishing phenomena in biology,” Rosell stated.

“This work paves the way for future studies and expands the routine use of examining mutations such as EGFR mutations as part of patient care,” Rosell added. u

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2015 AACR

PARP Inhibitor and PI3K Inhibitor Combo in Breast and Ovarian Cancers

N

ow that a number of targeted therapies are available for the treatment of cancer, one of the big questions is how best to combine them, especially for patients with few other treatment options.

Preliminary study shows that combining the PARP inhibitor olaparib with the investigational PI3K inhibitor BKM120 achieves reUrsula A. sponses in 2 aggressive cancer types that Matulonis, MD share a genomic landscape: high-grade serous ovarian cancer and triple-negative breast cancer. This preliminary study showed the feasibility of combining these 2 therapies, and further studies are ongoing.

Moving forward, combination of biologics will require understanding the genomic landscape and to figure out where these combinations fit.

“From a genomic commonality standpoint, there are similarities between high-grade serous ovarian cancer and triple-negative breast cancer. They share a common genomic landscape, with the presence of a high number of copy alterations. Preclinical studies suggested the synergy of these 2 drugs in cell lines, which led to the present study,” explained Ursula A. Matulonis, MD, Director and Program Leader of Medical Gynecologic Oncology at Dana-Farber Cancer Institute, Boston, MA. “The phase 1 study reassures us that it is possible to combine olaparib and BKM120 and that we have seen responses in women with triple-negative breast cancer as well as in women with high-grade serous ovarian cancer,” she continued.

This study, presented at the 2015 Annual Meeting of the American Association for Cancer Research, follows on the heels of preclinical data suggesting that the combination is more effective than either drug alone; both the preclinical studies and the phase 1 study are

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funded by the Stand Up to Cancer (SU2C) initiative.

“We could not have done these studies without SU2C,” she emphasized.

The first part of the study was a dose-escalation phase that included 46 patients (12 with breast cancer and 34 with ovarian cancer [90% with serous ovarian cancer]). Seventy-seven percent of patients had germline BRCA mutations. Median age of ovarian cancer patients was 60 years, and median age of breast cancer patients was 47.5 years. Of the breast cancer patients, 63% had triple-negative disease.

Of 10 dose levels tested in the dose-escalation phase, the maximum tolerated dose was 50 mg once daily of BKM120 and 300 mg/bid of olaparib. Overall, the combination was well tolerated. Dose-limiting toxicities of concern were grade 3 depression in 1 patient and grade 4 liver function test abnormality in another patient.

In the dose-expansion phase, nausea (79%) and fatigue (66%) were the most common adverse events.

Hyperglycemia occurred in 40%, depression in 22%, and anxiety in 19%.

“These central nervous system effects occur because BMK120 crosses the blood-brain barrier,” Matulonis said.

“An important finding of this study is that we saw responses in both BRCA-mutant and BRCA wild-type cancers. Further study is ongoing to identify biomarkers to select patients most likely to benefit from this combination,” she said.

Tumor shrinkage of greater than 30% according to RECIST was observed in about one-third of patients with either triple-negative breast cancer or high-grade serous ovarian cancer. In the ovarian cancer patients, partial response was seen in 26% of patients, and stable disease in 48%. In the breast cancer cohort, 5 patients achieved a partial response.

The next step is to study the PI3K inhibitor BYL719, which does not cross the blood-brain barrier, and determine whether this drug can be more safely combined with olaparib.

“Moving forward, combination of biologics will require understanding the genomic landscape and to figure out where these combinations fit,” Matulonis said. u

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Genomic Sequencing for Pancreatic Cancer

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ust because whole genome sequencing can be done on a patient’s tumor doesn’t mean that this will translate to a patient’s getting targeted therapy for identified genetic abnormalities, especially if that patient has pancreatic cancer.

In the Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) Trial, no patient with an identified genetic abnormality proceeded to targeted therapy.

Results were presented at the 2015 Annual Meeting of the American Association for Cancer Research and published in Clinical Care Research.

Pancreatic cancer is particularly difficult to treat.

The average lifespan if not treated is about 31 days, and 5-year survival is very poor. Thus, identification of targetable mutations might be a way to improve outcomes.

Of 93 patients screened in IMPaCT, 76 were eligible for whole genome sequencing. Of these, actionable targets were identified in 22 patients, and none went on to receive targeted therapy on the trial.

Reasons cited for the failure to get patients to targeted therapy include difficulty in obtaining adequate tumor tissue for biopsy, lag time in getting tumor tissue to the lab and back, short life span of pancreatic cancer patients, their desire not to be randomized if they have an identifiable genetic abnormality, urgency to get treatment as quickly as possible, and lack of teamwork among specialties involved.

The authors suggested that healthcare systems are not set up for expediting genomic results. “We are in the middle of a learning curve. The technology is ahead of what our healthcare systems can deliver. It will take

a long time for this to become a reality,” said lead author Lorraine A. Chantrill, MD, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.

In the Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) Trial, no patient with an identified genetic abnormality proceeded to targeted therapy.

The study screened for 3 molecular targets: HER2 amplification, KRAS wild-type, and mutations in DNA damage repair pathways (BRCA1, BRCA2, PALB2, ATM). Of the 76 patients screened, 17 were unsuitable for tissue processing for a variety of reasons, including ineligibility, objecting to randomization, and deaths due to pancreatic cancer.

Only 22 of those screened turned out to be candidate cases. Of the 22 patients with actionable targets identified, 6 died before results were obtained, and the other 16 could not get treatment for a variety of reasons.

To move the field along, the infrastructure has to change to incorporate the various specialties involved as a team, Chantrill said.

At present, the cost of multiple gene panels is not reimbursed by insurance companies, which is yet another hurdle. u

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EDITORIAL CLINICAL TRIAL

ASCO Launches First-Ever Clinical Trial: Aims to Learn from Patients with Advanced Cancer Who Lack Standard Treatment Options

Five Leading Pharmaceutical Companies Will Support Innovative Study, Contribute Drugs

T

he American Society of Clinical Oncology (ASCO) recently announced its first-ever clinical trial that will offer patients with advanced cancer access to molecularly targeted cancer drugs and collect real-world data on clinical outcomes to help learn the best uses of these drugs outside of indications approved by the Food and Drug Administration (FDA).

Plans for the Targeted Agent and Profiling Utilization Registry (TAPUR) study, including the participation of major pharmaceutical companies that will contribute free drugs, were released in a news briefing at the Society’s 2015 annual meeting in Chicago, IL. The ASCO-sponsored prospective, nonrandomized clinical trial will collect information on the antitumor activity and toxicity of commercially available targeted cancer drugs in a range of cancer types, including any advanced solid tumor, multiple myeloma, or non-Hodg­ kin lymphoma, with a genomic variation known to be a drug target.

“Oncologists often use therapies approved for a specific cancer indication to treat people with other types of advanced cancer, but we very rarely learn from that experience to benefit other patients,” said ASCO President Peter Paul Yu, MD, FACP, FASCO. “TAPUR will document the real-world experience of patients who receive commercially available targeted anticancer drugs and will describe the effectiveness and side effects of a range of targeted agents available in this study.”

ASCO will organize the operational aspects of the study, including the participation of multiple collaborators that are central to TAPUR’s success. TAPUR will involve not only patients and physicians, but also ASCO oversight committees, pharmaceutical companies, technology firms, and community-based study sites, representing a uniquely innovative and inclusive approach to studying the use of molecularly targeted cancer drugs.

“We are leveraging ASCO’s unique ability to bring together a diverse group of collaborators to undertake

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something that’s never been done before, all while simplifying access to multiple cancer treatments across many tumor types,” said ASCO Chief Medical Officer Richard L. Schilsky, MD, FASCO. “Perhaps even more importantly, TAPUR will involve community-based research programs, where the majority of cancer patients receive treatment, and will provide education and support to community oncologists to help them interpret complex genomic tests.”

ASCO will organize the operational aspects of the study, including the participation of multiple collaborators that are central to TAPUR’s success.

TAPUR Next Steps In the coming months, an Institutional Review Board will review the study protocol and consent form. In addition, ASCO has established 3 oversight committees, each of which will include patient representatives, clinical oncologists, statisticians, and genomics specialists: • Steering Committee to oversee study operations, establish data sharing and publication policies, review plans to add or remove drugs from the study, and approve participation of clinical study sites • Molecular Tumor Board to review the proposed drug-target match and suggest therapies on or off the study • Data and Safety Monitoring Board to regularly review study results to ensure that severe or unexpected adverse events are carefully monitored, determine when enrollment of study cohorts should expand or cease, and determine when to release data and to which parties.

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CLINICAL TRIAL

Patient Participation TAPUR is designed to include a broader patient population than is typically enrolled in clinical trials. It will accept patients who have any advanced solid tumor, multiple myeloma, or B-cell non-Hodgkin lymphoma and are no longer responding to standard anticancer treatment or for whom no acceptable treatment is available. Patients will be screened to determine if they are healthy enough to participate based on broad inclusion/ exclusion criteria.

Patients participating in TAPUR will receive the anticancer drugs at no charge. It is expected that routine clinical care costs will be covered by the patient’s insurance plan.

If and when a patient meets the defined trial criteria, his or her treating physician will select a drug from among those available in the TAPUR study protocol that targets the identified genomic variation in the patient’s tumor. If a relevant drug-target match is not described in the protocol, a physician may consult the Molecular Tumor Board, which will review the clinical and genomic features of the case and suggest potential therapies on or off the study. All patients who receive treatment through TAPUR will be monitored for standard toxicity and efficacy outcomes including tumor response, progression-free and overall survival, as well as duration of treatment.

Patients participating in TAPUR will receive the anticancer drugs at no charge. It is expected that routine clinical care costs will be covered by the patient’s insurance plan.

Participating Organizations ASCO has invited a number of pharmaceutical companies to provide marketed, targeted drugs and additional resources to support the development of the new study’s infrastructure. At the time of this announcement, ASCO reported that the following companies have signed memoranda of understanding agreeing to participate in the TAPUR study: • AstraZeneca • Bristol-Myers Squibb • Eli Lilly and Company • Genentech • Pfizer

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“At least 13 drugs that target more than 15 unique genomic variants will be provided by these companies. We are extremely grateful for the generosity of these companies, without whose support TAPUR would not be possible,” said Dr Yu. “We anticipate additional companies will sign on and are extremely encouraged with the level of interest we have received so far.”

ASCO will launch the TAPUR study at clinical sites that comprise the Michigan Cancer Research Consortium, the Cancer Research Consortium of West Michigan, and the Carolinas Healthcare System—existing research networks that run research trials for the National Cancer Institute and industry—with the ultimate goal of expanding nationally.

Two technology companies will provide key support to manage, analyze, and interpret the study data: Syapse will provide its Syapse Precision Medicine Platform to automate the study workflow and the Molecular Tumor Board process and capture structured data from participating practices. Illumina will provide its NextBio knowledge base platform to support and inform the case review by the Molecular Tumor Board, as well as support analysis of the TAPUR data by the study team.

Finally, the Society will collaborate and share data with the Netherlands Center for Personalized Cancer Treatment, which is conducting a clinical trial using a study protocol very similar to TAPUR. “We are very fortunate that this leading cancer center has the same focus as TAPUR,” said Dr Schilsky. “Technological advancements will allow us to pool our information in a seamless fashion and give us the ability to learn from the experience of a larger group of patients.”

Patient Advocates to Play Key Role in TAPUR Patient advocates will play a central role throughout the study, providing guidance and oversight support.

Jane Perlmutter, PhD, a cancer survivor and nationally recognized patient advocate, is lending her expertise in trial development and will help coordinate patient advocate recruitment and training for the study.

“TAPUR has enormous potential to improve our understanding of the effectiveness of currently available therapies in treating cancers with genomic variations and to learn from patients who are treated with off-label drugs,” said Dr Perlmutter. “I applaud ASCO for undertaking this important study and believe its findings will improve cancer care, especially for those with advanced cancer for whom traditional therapies are no longer working.”

For more information about TAPUR, please go to www.asco.org/TAPUR. u

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